Diagnosis and treatment of tissue

ABSTRACT

A system and method for testing tissue in a patient. An optical probe illuminating the tissue generates reflected light corresponding to the illuminated tissue. A spectrometer and a tissue classification system provide a diagnostic classification. A treatment device delivers treatment to the tissue while the probe is in position to sense the reflected light.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/202,860 filed on Jul. 6, 2016 and now U.S. Pat. No. 9,814,449, whichis continuation-in-part of U.S. national stage application Ser. No.14/400,942, filed Nov. 13, 2014 and now U.S. Pat. No. 9,814,448, ofInternational Patent Application No. PCT/US2013/041858, filed May 20,2013, which claims the benefit of U.S. Provisional Application No.61/649,694, filed May 21, 2012, the entire disclosures of which areincorporated herein by reference; and application Ser. No. 14/400,942 isa continuation-in-part of U.S. application Ser. No. 13/898,062 filed onMay 20, 2013, which claims the benefit of U.S. Provisional ApplicationNo. 61/649,694, filed May 21, 2012, the entire disclosures of which areincorporated herein by reference; and U.S. application Ser. No.15/202,860 claims the benefit of U.S. Provisional Application No.62/189,542, filed Jul. 7, 2015, the entire disclosures of which areincorporated herein by reference.

SUMMARY

In one form, a system according at least one embodiment of the inventiontreats tissue in a patient by a user. An optical probe has at least onelight source configured to illuminate the tissue and at least one sensorfor sensing reflected light from the tissue. A spectrometer configuredto analyze the reflected light produces spectroscopic data. A tissueclassification system comprising at least one algorithm correlatesselected data of the spectroscopic data with a diagnosis classification.The tissue classification system provides the diagnosis classificationto the user. The optical probe includes a treatment device configured toallow therapeutic treatment to be delivered to the tissue by thetreatment device while the optical probe is in position to sense thereflected light for the diagnosis classification.

In one form, a method according at least one embodiment of the inventiontreats tissue in a patient by illuminating the tissue with an opticalprobe including at least one sensor for sensing reflected light from thetissue and transmitting reflected light information to a spectrometerconfigured to analyze the reflected light information producingspectroscopic data. A diagnostic classification of the tissue isreceived from a tissue classification system including at least onealgorithm that correlates selected data of the spectroscopic data withclassification data to determine the diagnostic classification. Thetissue is treated with the use of the optical probe based on thereceived diagnostic classification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 illustrate positioning of the cryoneedles within prostatetissue for either whole-gland therapy or focal therapy purposes. FIG. 1is schematic representation of a transverse view plus ultrasound imageof an array of cryoneedles, and FIG. 2 is an ultrasound image of alongitudinal view of FIG. 1 showing an array of cryoneedles (striated).

FIG. 3 illustrates strategic placement of a brachytherapy needle, suchas to locate radioactive pellets within the prostate.

FIG. 4 illustrates brachytherapy in which radioactive pellets have beenlocated within the prostate.

FIG. 5A illustrates a photograph of a three-dimensional (3D) opticallymapped image of the prostate following optical measurements identifyinglocations of prostate cancer lesions according to one embodiment.

FIG. 5B corresponds to FIG. 5A and illustrates in a simplified linedrawing of a perspective view of die three-dimensional (3D) opticallymapped image of the prostate shown in FIG. 5A; FIG. 5B is provided toillustrate some of the details of FIG. 5A.

FIGS. 6 and 7 illustrate a coronal view of brachytherapy template and aprostate gland, and a sagittal view of the template, optical probe arrayincluding optical sensors, prostate gland, and USP according toembodiments.

FIG. 8 illustrates a 2×2 fiber optic probe array with optical sensors onthe left side and the 2×2 filler optic probe array with optical sensorsin combination with a brachytherapy template or similar on the rightaccording to one embodiment.

FIG. 9 illustrates a right side view and a top view with a portion cutaway of a tip of a fiber optic probe according to one embodiment.

FIG. 10 illustrates a block diagram of an imaging system to diagnose andidentify cancer lesions of the prostate according to one embodiment.

FIG. 11 illustrates the typical fluorescence spectra of prostate tissuesfor 290 and 340 nm excitation where peaks 102, 104 and 106 correspond totryptophan, collagen, and NADH 104. X-axis represents emission spectrameasured between 300 nm and 550 nm and Y-axis represents normalizedintensity measured between 0.01 and 0.09.

FIG. 12 illustrates typical diffuse reflectance spectra of prostatetissue. Each scan represents diffuse reflectance spectra obtained fromdifferent locations.

FIG. 13 illustrates in block diagram form one embodiment of an opticalsystem connected to an optical probe and a computer controller executinguser interface software and a tissue classification algorithm.

FIGS. 14-15 illustrate fluorescence intensity spectra of prostate tissueat 290 and 340 nm excitation being processed for analysis andclassification, with fluorescence intensity (counts) along the y-axisand wavelength (nm) along the x-axis.

FIGS. 16-17 illustrate normalized fluorescence intensity spectra ofprostate tissue at 290 and 340 nm excitation being processed foranalysis and classification, with normalized fluorescence intensityalong the y-axis and wavelength in nanometers (nm) along the x-axis.

FIGS. 18-19 illustrate percentage variability in fluorescence spectralabeled X and histopathology data labeled Y associated with partialleast square (PLS) components at 290 nm and 340 nm variability, withpercent variance along the y-axis and number of partial least square(PLS) components along the x-axis.

FIG. 20 shows typical normalized diffuse reflectance spectra scans ofprostate tissue within the range of 550 nm-700 nm, with normalizedintensity along the y-axis and wavelength (nm) along the x-axis.

FIGS. 21-22 illustrate the percentage variability in diffuse reflectancespectra labeled X and histopathology data labeled Y associated with 1 to12 PLS components for benign versus malignant and high grade versus lowgrade prostate tissue classification, respectively, with percentvariance along the y-axis and number of PLS components along the x-axis.

FIG. 23 illustrates in block diagram form one embodiment of an opticalsystem connected to an optical probe and a computer controller executinguser interface software and a tissue classification algorithm, incombination with an imaging system.

FIG. 24B illustrates two photographs, the lower photo 343A is an MRIimage where a cancer lesion was first diagnosed by a radiologist and theupper photo 343B is a MRI fusion image showing a cancer lesion fusedwith an ultrasound (US) image. FIG. 24A illustrates one photograph 340Awhich illustrates elastic scattering spectra captured from the locationor vicinity of the cancer lesion shown in MRI/US fusion image 343B. Whenthis spectrum is processed by a tissue classification algorithm, it caneither confirm or contradict the existence of cancer lesion shown inMRI/US fusion image for 3D optical mapping of the prostate.

FIG. 25B illustrates two photographs, the lower photo 343C is an MRIimage where a cancer lesion was first diagnosed by a radiologist and theupper photo 343D is a MRI fusion image showing a cancer lesion fusedwith an ultrasound (US) image. FIG. 25A illustrates one photograph 340Bwhich illustrates fluorescence spectra captured from the location orvicinity of the cancer lesion shown in MRI/US fusion image 343D. Whenthe spectra is processed by a tissue classification algorithm, it caneither confirm or contradict the existence of cancer lesion shown inMRI/US fusion image for 3D optical mapping of the prostate.

FIG. 26 illustrates in one form the components of the ClariCore™ System.

FIG. 27 depicts in one form the ClariCore™ System and its clinicalplacement.

FIGS. 28A and 28B illustrate the normal/suspicious optical readingmonitor display achieved by applying a classification algorithm todetermine if the tissue is ‘Suspicious’ at each increment movement ofthe needle.

FIG. 29 illustrates in one form the OBN composed of a 16-gauge (1.59 mm)stainless steel cannula with an open beveled-tip configuration and aslightly smaller diameter (1.36 mm) inner needle with embedded opticalfiber and a space for sample collection (19 mm sample notch), cablewraps and connectors.

FIG. 30 illustrates in one form the lip of the OBN containing the singleexposed fiber as an optical sensor for light source and detection. Theouter beveled Cannula overlays the Inner Needle and is used to shear andcollect tissue samples.

FIG. 31 illustrates in one form the sample notch (e.g., collection spaceof 19 mm) at the distal end of the inner needle used to chamber theexcised biopsy core.

FIG. 32 illustrates in one form the Handpiece and OBN having integratedfiber optics, and electrical and optical cabling to interface with thesystem Console. The Handpiece is an enclosed assembly that houses theOBN (ref). The Handpiece contains electro-mechanical interlaces (motorand chassis) and has three operational buttons by which the physiciancontrols the advancement of the Inner Needle and Cannula into selectedregions of the prostate tissue under TRUS guidance.

FIG. 33A illustrates in one form a side view of the interior of theHandle housing showing the stepper motor for auto-advancing the innerneedle in 1 mm increments up to 22 mm. The cannula through which theinner needle passes is mechanically driven by a spring, and manuallyretracted and released. The cannula can also be retracted and releasedautomatically via a combination of being driven by a motor or spring andcontrolled by computer.

FIG. 33B illustrates in one form a plan side view of the Handle showingthe various buttons.

FIG. 34 shows in one form the modules of the Console and the hardwareinterfaces controlled by the Host and MCU Processors.

FIG. 35 illustrates in one form each functional block of the systemrepresenting an independent software item of the console (note: theembedded software for the spectrometer and excitation source areseparate).

DETAILED DESCRIPTION

The American Cancer Society estimates that in the United States in 2013,238,590 new cases of prostate cancer (PCa) will be diagnosed comparedwith approximately 99,000 cases diagnosed in 1988 attributable to theadvent of prostate-specific antigen (PSA) screening. Consequently, therehas been stage migration with earlier stage at diagnosis. Presently, 92%of incident PCa are locoregional versus metastatic. Hence, only 29,720men are estimated to the from this disease in 2013. Accurate stagingbefore treatment is desirable given the relatively high number of menwho must be treated to prevent PCa-specific death. PCa has a longlatency period and consequently more men the with rather than from thisdisease. Hence, a significant proportion of US men with localized PCaare overdiagnosed and overtreated with attendant morbidity andsignificant cost escalations as insignificant tumors were detected viaaggressive screening procedures.

Transrectal ultrasound (TRUS) guided tissue biopsy of the prostate isthe current method of screening for PCa. Pathological examination oftissue needs to confirm the presence of the disease. However, prostatebiopsies are subjected to serious sampling errors and frequently missaggressive PCa that warrant definitive therapy during initialscreenings. The PCa detection rate according to the current standard ofcare for TRUS-guided needle biopsies with 10-12 biopsy cores is only25-30%, while more than 50% of cancers that require definitive treatmentremain undetected during initial biopsies. Such undetected cancers dueto false negative biopsies are at risk of spreading beyond the prostategland and metastasizing to distant sites. Even when PCa were diagnosedby prostate biopsies, they may fail to provide accurate informationregarding histologic grade and stage of the disease that are needed fortherapeutic decisions. Aggressive PCa lesions may be differentiated fromnon-aggressive or latent PCa based on histologic grade, pathologicstage, and volume. Aggressive PCa for organ-confined disease may bedefined as those tumors with volume ≥0.5 cc or Gleason⁸ sum ≥7.

An optical probe array (e.g., a needle having an integrated opticalsensor at its tip) is used in combination with an image guiding system(e.g., an ultrasound system) and/or in combination with an imagingsystem (e.g., fluorescence and/or diffuse reflectance spectroscopy) toobtain in vivo optical spectroscopically-guided prostate analysis and/ortreatment. This enables one to sample and diagnostically classifydifferent types of tissue within the prostate. The optical probesinterface with a device, such as a fluorometer or fluorescencespectroscope, used to measure light parameters, such as fluorescence. Inone embodiment, software to control a fluorometer, an optical dataacquisition device, a user interface, and a tissue classification systemresides on a laptop computer. In one configuration, the fluorometercomprises two light sources with peak emissions respectively at 280-290and 340 nm, one broadband light source 500-1000 nm and a spectrometer(e.g., CCD-based (charge coupled device), PMT-based (photon multipliertube), etc.). Systematic application of this technology uses opticalmeasurements to indicate presence of cancer or other abnormal tissuewithin the prostate permitting determination of highest histologic gradeand stage of the disease at the time of biopsy and permitting targetedtreatment. In addition, based on the number of positive cores andpercentage core involvement, embodiments provide information regardingsize (volume), location, and distribution of PCa. In at least somesituations this information can be combined to determine if a patienthas aggressive disease or not and hence to customize therapeutic optionsto meet the needs of each patient.

Embodiments significantly improve diagnosis, staging, and therapy of PCainvolving the following: 1) Accurate diagnosis and localization of PCalesions using a TRUS-guided standard biopsy, MR/Fusion biopsy,saturation biopsy, or brachytherapy template-guided mapping biopsy usingoptical biopsy needle and associated technology, 2) Determine whetherpatient has aggressive PCa based on histopathological grade, pathologicstage, number of positive cores, and percentage core involvement, 3)Personalized therapy and when applicable adjunct with an optical probeand associated technology, and 4) Monitor response during therapy andprogress following therapy. Based on histopathological findings frombiopsy tissue, patients with aggressive PCa lesions that requiredefinitive, potentially curative treatment which may include surgery,radiation, and neoadjuvant therapy can be identified. The aim ofneoadjuvant therapy is to maximize cure rates for patients who haveundergone definitive therapy for localized disease, theoretically byeliminating micrometastatic disease. Patients assessed to havenon-aggressive disease may be candidates for watchful-waiting (WW) oractive surveillance (AS). We believe this approach is a vital step tominimize overtreatment of PCa according to the current standard of caresince 5 out of 6 men diagnosed with PCa may be candidates for WW or AS.It will also lead to early diagnosis of clinically important cancer andgives an opportunity to intervene where therapy benefits the patient.

Definitive whole-gland therapy for PCa has serious side effectsincluding erectile dysfunction (ED) and urinary incontinence. Theconcept of “highly selective” ablative procedures or targeted focaltherapy (TFT) for PCa is being considered in certain low-risk patients.During TFT, therapeutic agent is targeted directly onto each PCa lesionor regions within the prostate instead of the entire gland. This optionwould hypothetically result in a significant decrease in the morbidityassociated with PCa treatment, particularly ED. The process of TFTincludes careful three-dimensional (3D) mapping of PCa lesions withinthe prostate gland followed by focused targeted treatment to only thoselesions or regions where PCa lesions are located. However, screeningpatients for this procedure is a challenge. Further, guiding treatmentbased on TRUS-guided biopsy findings is difficult due to prostatemovement and deformation or warping. Using 3D computer models of autopsyprostates with previously undetected carcinomas, it has been proven thattransperineal mapping biopsy (TMB) as the method to identify patientswith low-risk PCa for TFT (e.g., positioning of cryoneedles 10 withinprostate tissue 11 following transperineal mapping biopsy procedure).FIG. 1 is schematic representation of a transverse view, and FIG. 2 isan ultrasound image of a longitudinal view of an array of cryoneedles(striated) 10.

In one embodiment, a 5-mm grid transperineal mapping biopsy consistentlysampled the highest Gleason grade 4/5 tumors and detected aggressive PCawith sensitivity, specificity, positive predictive value (PPV), andnegative predictive value (NPV) of 95%, 30%, 31%, and 95%, respectively.Specificity and positive predictive value were lower since thetransperineal mapping biopsy detected a higher proportion of clinicallyinsignificant PCa lesions.

By combining an optical biopsy needle and/or an optical probe withtransperineal mapping biopsy, similar diagnostic information regardingtumor locations and tumor distribution can be obtained enablingtherapeutic agents to be directed to these same locations for targetedfocal therapy (TFT). This document describes diagnostic and therapeuticmodalities based on the optical probe and associated technologies forTFT for low risk PCa cancer patients sparing them serious side-effectsassociated with definitive therapies such as surgery and radiation.

Therapeutic Modalities

Cryotherapy:

Cryoablation of the prostate may be used to treat localized prostatecancer or recurrences after previous treatments. Cryoablation of theprostate may be done through total freezing of the prostate.Alternatively, cryoablation may be restricted to focal or regionalfreezing to treat only the involved areas of the prostate as in TFT. Inthis manner the nerves for erection sitting on the uninvolved pan of theprostate may remain intact to preserve erections. Cryotherapy has beenperformed worldwide for over 50 years. The American and EuropeanAssociation of Urology guidelines on prostate cancer state thatcryotherapy is a true therapeutic alternative for patients withclinically localized prostate cancer. The American Association ofUrology recently made an announcement of a best practice statementconfirming cryotherapy as a valid treatment option for both primary andrecurrent localized prostate cancer. In 2005 in the UK, the NationalInstitute of Clinical Excellence approved the use of cryotherapy forpatients with prostate cancer, both as a primary treatment and assalvage treatment after radiotherapy or hormone therapy.

Cryotherapy causes cell death through two principle mechanisms. First,as the temperature falls, extracellular ice crystallizes causingmovement of water from the intracellular to the extracellularenvironment after an osmotic gradient. As the temperature continues tofall, intracellular ice crystals form, causing direct damage to theintracellular organelle system and the cell membrane. The secondmechanism is platelet aggregation and microthrombus formation in smallblood vessels, which leads to ischemic change in the tissue areasupplied by the affected blood vessels. These changes lead tocoagulative necrosis and cause a well demarcated lesion. In addition,severe temperature changes and ischemic change induce apoptosis in cellsat the periphery of the cryolesion.

The effectiveness of the cellular destruction depends on rapid freezing,the lowest temperature reached, and slow thawing. This is generallyachieved through two freeze—thaw cycles to a target temperature of −40°C.

Cryoablation of prostate cancer first took place in 1968 using probescooled by liquid nitrogen in a closed system. The early technique wasassociated with considerable complications, such as rectourethralfistulas, urethral sloughing and urinary incontinence. With theintroduction of TRUS guidance and the urethral warming catheter,improved results have been achieved. The subsequent development ofcryotherapy using 17-gauge needles with echogenic tips has allowedcontrolled and accurate delivery of the treatment. The current systemuses high-pressure argon and helium gas for freezing and warming,respectively. The temperature change is governed by the Joule-Thompsoneffect, whereby high-pressure gases, when forced though a very smallopening into a low-pressure area (within the tip of the cryoneedles),undergo specific temperature changes. This allows the freezing andsubsequent thawing of the prostate using the same needle. During thetreatment, the temperature in different areas of the prostate ismonitored in real time by means of interstitial thermosensors. Theneedles are placed under TRUS guidance through the skin of the perineumusing a brachytherapy template without the need for tract dilatation andwith minimal trauma to the patient. As the gas is delivered through thespecialized needles, it cools the prostate tissue rapidly to the targettemperature of −40° C. The ice ball is clearly visible on TRUS as itforms and is monitored continuously throughout the procedure. The use ofurethral warmer reduces the incidence of urethral sloughing.

Cryotherapy following 3-D mapping of PCa lesions using optical probeswith optical sensors and associated system to treat tissue identified ina generated image as noted herein will allow accurate real-time readingand staging of the tumor, directing treatment to the areas affected byPCa (FIGS. 1-2). As noted above, FIGS. 1 and 2 illustrate positioning ofthe cryoneedles for whole-gland or focal therapy procedure. FIG. 1 isschematic representation of a transverse view plus ultrasound image, andFIG. 2 is an ultrasound image of a longitudinal view of the array ofcryoneedles (striated) 10. It should be noted that prostate cancerlocalization and cryoablation or another form of therapy is not onlylimited to transperenial procedure. In some embodiments, a TRUS(transrectal ultrasound) system of cancer localization and immediateapplication of therapy through the mapping or biopsy needle oralternatively an independent catheter is contemplated.

Careful mapping of the prostate can be done using the brachytherapy gridthat separates areas of the prostate by 0.5 cm allowing adequatetherapeutic ice ball formation. The longitudinal area that will besurveyed by the optical probe will define every 0.5-1.7 cm the presenceof PCa cells. The average prostate biopsy core is 1.7 cm and the averagelength of the prostate is approximately 4 cm.

Ultimately, biopsies will not be needed once correlation between PCa andoptical probe is established, allowing intra-operative survey andassessment of tumors to be treated by cryoablation. The result of thiswork decreases the rate of complications or side effects due tocryotherapy, i.e.; erectile dysfunction, urinary incontinence andrectourethral fistula. TFT with recurrent treatment will be availableallowing all procedures to be performed as outpatient basis increasingpatient satisfaction and decrease cost of treatment.

Optical probes will be placed in the prostate using the brachytherapytemplate. Following identification or confirmation of tumors and tumormargins within the prostate, cryoprobes or brachytherapy needles withradioactive pellets are strategically placed for TFT applications (FIGS.1-2 for cryotherapy and 3-4 for brachytherapy). For example, FIG. 1 maybe a schematic representation of a transverse view plus ultrasound imageof strategic placement of cryoprobes, and FIG. 2 is an ultrasound imageof a longitudinal view of the array of cryoprobes (striated) 10. Forexample, FIG. 3 illustrates strategic placement of a brachytherapyneedle 41 within a prostate 42, such as to locate radioactive pelletswithin the prostate 42, under the guidance of an ultrasound probe 43within the rectum 44. FIG. 4 illustrates brachytherapy in whichradioactive pellets 45 have been located within the prostate 42 about atumor 46 relative to a bladder 47 and relative to a seminal vesicle 48.

FIG. 5A illustrates a photograph of a three-dimensional (3D) opticallymapped image of the prostate following optical measurements identifyinglocations of prostate cancer lesions according to one embodiment. FIG.5B corresponds to FIG. 5A and illustrates in a simplified line drawingof a perspective view of the three-dimensional (3D) optically mappedimage of the prostate shown in FIG. 5A; FIG. 5B is provided toillustrate some of the details of FIG. 5A.

FIG. 5A provides information which can serve as a precursor to aprostate biopsy or to guide therapy. In this context, optical biopsyneedles (see needle tracks 52 which are on the near side of lesions 56,needle tracks 53 within the lesions 56, and needle tracks 55 on the farside of the lesions 56) are inserted in to a prostate gland 54 guided bya brachytherapy or another template. This template is located intransperineal direction and 5 mm and 10 mm or other grid points areprovided for needle insertions. Optical spectroscopy measurements areobtained in discrete or continuous modes to detect cancer. Each gridcoordinate and depth where lesions 56 are located will be recorded fortherapeutic applications. Alternatively, lesions 56 may be treated asthey are detected by laser ablation or photodynamic therapy using theoptical biopsy needle 52.

In FIG. 5B, the partial cylinder 54B is intended to represent a portionof the prostate gland 54 shown in FIG. 5A. The sphere 56B is intended torepresent the lesion 56 shown in FIG. 5A. The rods 52B represent theneedle tracks 52 which are on the near side of lesion 56 shown in FIG.5A. The rods 53B shown in phantom represent the needle tracks 53 whichare within the lesion 56. The rods 55B represent the needle tracks 55which are on the far side of lesion 56.

The whole prostate should be surveyed with the optical probetransversally and longitudinally using the TRUS probe in different viewsand detect continuous read from the optical sensors mounted on theoptical probe Pre-operative measurements of the prostate aid theplacement of cryoneedles but also the previous biopsy report withhistopathological data may help the surgeon concentrate attention in theareas proven to be positive for PCa.

Embodiments include several modifications to a needle (e.g., a biopsyneedle) such as an optical probe with optical sensors, and associatedtechnology to accommodate critical needs in cryotherapy applicationsincluding TFT. These embodiments will be discussed in further detailsherein.

-   -   1. Optical probe with multiple sensors separated by 5 mm or at        greater or less spacing intervals.    -   2. Probe with either single or multiple sensors in motorized 2×2        or 3×3 configurations for transperineal forward/backward        movement.    -   3. Optical needles in motorized 2×2 or 3×3 configurations for        transperineal forward/backward movement.    -   4. Hardware and software modifications to fluorometer to        accommodate configurations 1 and 2.    -   5. Above arrangement requires careful mapping of the prostate        followed by cryoablation. Alternative configuration may be an        integrated optical sensor and cryoneedle to concurrently achieve        PCa diagnosis followed by cryoablation of those lesions.

Photodynamic Therapy:

Another minimally invasive treatment modality for PCa patients isphotodynamic therapy (PDT). PDT is a treatment that usesphotosensitizing drugs; these agents are pharmacologically inactiveuntil they are exposed to near infrared (NIR) light in the presence ofoxygen. The activated drug forms reactive oxygen species that aredirectly responsible for tissue destruction around the area exposed toNIR light. For PCa, the photosensitizers can be administered orally orintravenously, and are activated in the prostate by NIR light of aspecific wavelength. This light is produced by a low-power laser or LED,and is delivered to the prostate using optical fibers within transparentplastic needles. The placement of the needles within the prostate isusually guided by transrectal ultrasound and brachytherapy template, andthe procedure is normally performed under general anesthetic. Energy iseither delivered via a cylindrical diffuser, which emits light along alength of fiber, or via a bare-tipped fiber, where the light comes outof the end only.

The photosensitizing drugs available vary in their modes of action. Somedrugs are tissue-based photosensitizers, and take a number of days toreach maximal concentration in the target organ. These drugs tend toaccumulate in the skin, where they can be activated by sunlight orartificial room light for a number of weeks after administration;patients who receive these drugs require protection from light until thedrug has been completely cleared from the skin. Other photosensitizersare activated in the vasculature; these drugs are activated withinminutes of light delivery, and are cleared rapidly. This quick clearanceallows the drug and light to be administered in the same treatmentsession, and avoids the need for prolonged light protection.

Embodiments include several modifications to the optical probe andassociated equipment to facilitate PDT for TFT applications to treattissue identified in a generated image as noted herein:

-   -   1. Addition of an LED at NIR range to fluorometer to deliver        light to PCa;    -   2. Modifications to software to facilitate above 1; and    -   3. Modifications to probe with single or multiple sensors to        deliver NIR light to PCa for therapeutic efficacy.

Brachytherapy (See FIG. 4 which Illustrates Brachytherapy in whichPellets have been Placed within the Prostate):

Brachytherapy (the term is derived from the Greek word brachys, whichmeans brief or short) refers to cancer treatment with ionizing radiationdelivered via radioactive material placed a short distance from, orwithin, the tumor. In PCa, brachytherapy involves the ultrasound- andtemplate-guided insertion of radioactive seeds into the gland. Permanentseed brachytherapy, also known as low dose rate brachytherapy, involveshaving tiny radioactive seeds implanted in the prostate gland. Radiationfrom the seeds destroys cancer cells in the prostate over time. Inaddition to permanent brachytherapy, temporary brachytherapy has alsobeen used. In this technique, the implants deliver radiation to theprostate at a higher dose rate than is provided by a permanent implant.Currently, the isotope most commonly used for temporary brachytherapy isiridium (Ir)-192, which provides a higher dose of radiation than theiodine (I)-125 anti palladium (Pd)-103 permanent implants. Low dose rateprostate brachytherapy is an effective treatment for localized PCa.Recently, it has been considered for use in a focused manner wherebytreatment is targeted only to areas of prostate cancer. The objective offocal brachytherapy for potential TFT applications is to provideeffective cancer control for low-risk disease but with reducedgenitourinary and rectal side-effects in a cost-effective way.Embodiments include modification to the technology to facilitate focalbrachytherapy for TFT applications. At least two configurations can beincorporated to treat tissue identified in a generated image as notedherein:

-   -   1. Removable probe with a single sensor coupled with a cannula        (outer needle). This is inserted via brachytherapy template        until a PCa lesion is located. Sensor is then removed and a        radioactive seed is inserted into the outer cannula. It is then        pushed via metal tubing to the exact location where PCa lesion        is located.    -   2. Probe with a seed-notch coupled with an outer needle. In this        mechanism, radioactive seed is already hidden inside the notch        covered by the outer needle. Once the sensor locate PCa lesion,        trigger mechanism fires and leave the radioactive seed where PCa        lesions is located.

HIFU:

Similar TFT applications may be achieved using high-intensity focusedultrasound (HIFU). HIFU is a treatment that uses ultrasound wave energyfocused on the prostate via a transrectal probe to treat tissueidentified in a generated image as noted herein. Multiple focal areas ofdestruction are created within the prostate. The prostate tissue isdestroyed through coagulation by the ultrasound wave energy causingrapid heat elevation to about 90° C. at the focal point. An opticalbiopsy needle and/or an optical needle probe may be used separately oras an integrated device for HIFU treatment of PCa in TFT applications.

AC/DC Current for PCa Tissue Ablation:

Tumor efficacy is achieved by passing AC or DC current across PCa tissueby strategically placed electrodes to treat tissue identified in agenerated image as noted herein. An optical probe can be used foridentification of locations of PCa lesions and thereby enablingstrategic placement of the electrodes. In an alternative configuration,both the electrode and optical sensor may be an integrated unit enablingconcurrent diagnosis followed by ablation of each PCa lesion.

Laser Ablation:

Laser ablation could be yet another method to ablate the cancer tissueidentified within the prostate once the locations of the cancer lesionsare found in a generated image as noted herein. A variety of laser typeshave been developed for use in medical applications. These lasers may berouted to each PCa lesion using an optical needle probe with eithersingle or multiple sensors.

RF Ablation:

RF ablation is yet another method to treat the identified canceroustissue within the prostate gland to treat tissue identified in agenerated image as noted herein. RF ablation is currently approved fortreatment of BPH (benign prostate hyperplasia) and is commerciallyavailable.

Vapor Ablation:

Vapor ablation is a modality to treat cancer or other type of abnormaltissues within the body such as to treat tissue identified in agenerated image as noted herein. Instead of using electrical, laser, ortissue freezing modalities, vapor with high temperature is used toshrink tissue or tumor.

Local Drug Delivery:

once the 3D mapping system has identified the location of canceroustumor within the prostate, using the same or another needle, drugs andpharmaceutical agents could be delivered as means of treating the cancerlocally.

3D Optical Imaging

FIGS. 6-10 illustrate one embodiment of a system for use with a patientin the lithotomy position. FIG. 6 illustrates a coronal view of abrachytherapy template 71, a prostate gland 72, and an ultrasound probe(USP) 73. FIG. 7 illustrates a sagittal view of the template 71, anoptical probe array 74 including optical sensors 75, the prostate gland72, and the ultrasound probe 73 according to embodiments. In oneembodiment, the template 71 may have alternating columns of openings ofdifferent diameter to accommodate different size probes, although anysize opening and any type of hole configuration may be pan of thetemplate 71.

FIG. 8 illustrates tips of a 2×2 fiber optic probe array 74 with opticalsensors 75 shown in a partial exploded view and the 2×2 fiber opticprobe array 74 with optical sensors 75 in combination with a perineal13×13 grid template 74 according to one embodiment.

FIG. 9 illustrates a right side view and a top view with a portion cutaway of a tip of a fiber optic probe 76 according to one embodiment. Inone embodiment, the probe 76 comprises a hollow tube or shaft 77, alight source comprising a transmitting fiber optic 78 positioned withina bore 79 of the hollow tube 77 and supported by the shaft 77 toilluminate the tissue located near or at an end of the hollow tube or atangle with respect to the axis of the hollow tube, and a receivingoptical fiber 80 positioned within the hollow tube to detect light fromthe illuminated tissue. In one form, the fiber 80 transmits the detectedlight to an optical light sensor which is part of an optical system(e.g., see FIG. 10 and optical system 115, below). Alternatively or inaddition, light sensors may be positioned on the shaft 77. In one form,a distal tip 81 is tapered to facilitate insertion into the prostategland. In one form, the transmitter and receiver fibers can be the samefiber. An optical splitter to separate the transmitted and receivedlight can be located in the probe (disposable), within the cable(disposable), or within the system (as a capital or longer-lastingcomponent).

FIG. 10 illustrates a block diagram of a system for 3D imaging of theprostate according to one embodiment. The patient is positioned in thelithotomy position and a spatial template 111 or grid is placed againstthe perineum for aligning optical probes of an array 112 into apredetermined orientation relative to each other and relative to thetissue. The optical probe array 112 is guided into the prostate underimaging guidance (e.g. transrectal ultrasound probe 113 connected to animaging guidance system 114) so that the optical sensors are within theprostate gland. Thus, the imaging guidance system 114 identifies theposition of the optical probes of the array 112 relative to the prostatetissue. An optical system 115 which comprises at least one light sourceand at least one light detector (e.g. spectrometer) transmits to andreceives light from the optical probe array 112. Light received by theoptical system 115 is collected by the light sensor or detector, thendigitized and processed (e.g., through a diagnostic algorithm) giving anindication of tissue condition (e.g. the presence or absence ofdisease). Diagnostic information from the optical system 114 is thencombined with spatial information from the ultrasound probe 113 (e.g.probe and probe sensor positions within the prostate are stored). Oncean acquisition has been performed, the probe array 112 can be moved to anew site within the prostate to perform additional acquisitions. Withacquisitions covering sufficient volume of the prostate, athree-dimensional diagnostic imaging system 116 forms a 3D map of theimaged prostate gland based on the generated light signals and theidentified position of the optical probe 112. The imaging system 116and/or a 3D map displayed as an image on display 117 can be used toguide targeted therapeutic modalities to positions where lesions havebeen identified.

Among other things, the system includes an ultrasound transducer andsensor (e.g., probe 113) with ultrasound control system 114, an opticalprobe array 112 connected to an optical control system 115, a template111 or other spatial control device (e.g. a grid), a 3-D imaging system116 (e.g. a processor, memory user software, and graphical display) andan optional therapeutic modality system (e.g., a processor, not shown)for analyzing the test results. A fluorometer (not shown), spectrometer(not shown) or other optical phenomena detecting device with userinterface software and tissue classification algorithm may be part ofthe optical system 115.

In one embodiment, the optical system 115 includes light sources such asLEDs, broadband tungsten-halogen or xenon lamps or lasers that transmitlight to the tissue under examination through at least one opticalfiber. Light reflected or emitted from the tissue under examination isrouted via optical fiber or fibers to at least one optical detector orsensor of the optical system 115. The light sources and detectors arecontrolled by the optical system 115 which comprises a processor,memory, and communication components similar to a computer. The opticalprobes of the array 112 are positioned adjacent to or inserted intoinside the prostate (or other tissue) through a transperineal gridtemplate or other methods in order to create a 3-D image of the prostatebased on tissue fluorescence and or based on any other type of lightspectroscopy measurements based on scattering phenomena of the tissue toreflect, shift (Raman scattering), absorb or scatter light or otherenergy (e.g., ultraviolet). In general, it has been found that thetissue is somewhat translucent and that when the tissue is illuminatedwith light energy, the energy tends to penetrate about 0.3 mm to 3.0 cm,depending on the wavelength and intensity. In addition, depending onwavelength and tissue composition, some tissue tends to fluoresce orotherwise provide excitations of varying wavelengths or other opticalphenomena. Other energy may result in different penetration andresponse, depending on the type of tissue, its location and composition.

Using the spectroscopy measurements, tissue abnormalities are identifiedand mapped. For example, using fluorescence spectroscopy. NADH,tryptophan, and collagen components of the tissue will be identified ascorrelated to tissue abnormalities and mapped. Similarly, diffusereflectance, scattering or absorptive light also provide irregularitiesand discontinuities in cell nuclei, cellular boundaries, etc., andpresence/absence of various proteins as correlated to tissueabnormalities. This information can be translated for tissueclassification for the purpose of identifying benign, malignant,calcified, and other components are labeled within the 3D opticalmapping image.

There are a number of endogenous fluorophores available in human tissue(See Table 1, below). FIG. 11 illustrates the typical fluorescencespectra of prostate tissues for 290 and 340 nm excitation where peaks102, 104 and 106 correspond to tryptophan, collagen, and NADH 104.X-axis represents emission spectra measured between 300 nm and 550 nmand Y-axis represents normalized intensity measured between 0.01 and0.09. Collagen spectra can be obtained by excitation of tissue with alight source at 320-340 nm. NADH spectra can be obtained by excitationof tissue with a light source at 350-370 nm. As illustrated in FIG. 11,tryptophan spectra 102, collagen spectra 104, and NAHD spectra 106register peak values at approximately 350 nm, 400 nm, and 460 nm,respectively.

FIG. 12 illustrates typical diffuse reflectance spectra of prostatetissue for three different scans 1-3 taken by an optical probe array atthree different locations within the prostate gland. Each scanrepresents diffuse reflectance spectra obtained from differentlocations. Diffuse reflectance spectra (DRS) provide architecturalinformation about the tissue rather than chemical composition. Lightphotons scatter, bounce, and even gel absorbed by the tissue. Diffusereflectance spectroscopy, sometimes known as Elastic ScatteringSpectroscopy, is a technique that measures the characteristicreflectance spectrum produced as light passed through a medium. Theprimary mechanisms are absorption and scattering, both of which varywith wavelength to produce the reflectance spectrum that is recorded.This spectrum contains information about the optical properties andstructure of the medium being measured.

FIG. 12 illustrates typical DRS spectra of prostate tissue capturedbetween 350 nm-700 nm inclusive of visible (VIS) range along the x-axisand intensity counts per second along the y-axis as a result ofilluminating the tissue with a broadband light source having awavelength range of at least 350 nm to 700 nm. Counts on y-axis are themeasure of intensity at each wavelength. The spectrum is measuredbetween 350-700 nm range at 5 nm intervals. The range along the x-axis(independent variable) is chosen and the intensity on y-axis (dependentvariable) is measured.

There are two absorption features approximately 425 nm and 650 nm andvariation in the slope between 475 nm-650 nm. If a broader band lightsource is used to illuminate the tissue (e.g., 350 nm to 1200 nm),additional features may be available from 700 nm-1200 nm (not shown)inclusive of near infrared (NIR) as well. These features may be utilizedfor prostate tissue classification. DRS primarily probes morphologicalfeatures and has proven to be sensitive to histological grades. Gleasongrade, which characterizes aggressiveness of PCa lesions based onglandular architecture, is a valuable prognostic variable. Patients withPCa of Gleason grade 4 or 5 are known to have poor clinical prognosis.Since light is scattered at cells or intracellular structures, DRS datacontains structural information of the medium. Hence, the structuralinformation in DRS can be used to differentiate low grade (Gleasonscore=6) from high grade (Gleason score≥7) carcinoma as well as classifybenign versus malignant tissue.

In one embodiment, a fluorometer has a connector where it cancommunicate with an ultrasound system used within prostate cancerdiagnostics and therapeutic procedures. User interface software is usedto capture 3D transrectal ultrasound (TRUS) images of the prostate. Gridcoordinates of brachytherapy template will be superimposed on 3D TRUSimage of the prostate. Software enables users to highlight each XYcoordinate position as well as Z coordinate (depth of the prostate) whencancer is identified. An optical probe is inserted into each gridcoordinate point and fluorescence spectra are captured using thefluorometer.

FIG. 13 illustrates in block diagram form one embodiment of an opticalsystem 132 such as a fluorometer connected to an optical probe 134 andconnected to a computer-based controller 136 executing user interfacesoftware and a tissue classification algorithm. The fluorometer 132transmits light from a light source or sources through the probe 134where light interacts with the tissue 138 and is received andtransmitted back to a detector inside the fluorometer 132. Thefluorometer 132 is operated by the computer-based controller 136 whichprocesses received signals and delivers via display 140 diagnosticclassification of the tissue under examination to the user. Thus, thedisplay 140 presents a graphical user interface which, in its simplestform, is a two or three-dimensional image of the tissue. Alternatively,the interface may provide the user with options so that die user canselect various images or perspectives of an image. For example, theinterface can give the user the option to select a two-dimensionalimage, a three-dimensional image, a fused image, or some other imagevariation. The interface can also provide the user with the option toselect a black-and-white image, a color image, a line image or otherimage parameter variations. Optionally, the system of FIG. 13 can beused in combination with an imaging system 141 such as an ultrasoundsystem or a MRI/CT system or both for identifying the position of theoptical probes relative to the tissue. (See also FIG. 23). A treatmentdevice 139 employing a treatment modality such as described herein canbe used in combination with the imaged or mapped tissue to treat theimaged tissue. For example, the device 139 can be a Cryotherapy device;a Photodynamic Therapy device, a Brachytherapy device; a high-intensityfocused ultrasound (HIFU) device; a tissue ablation device; a Laserablation device; a RF ablation device; a Vapor ablation device, and aLocal drug delivery device.

In one embodiment, when the tissue classification algorithm indicatesthat the location is positive for cancer based on fluorophorestryptophan, collagen, and NADH, an operator estimates the location(e.g., the depth of insertion on live TRUS image of the prostate) andhighlights corresponding XYZ coordinates in the 3D TRUS image on thefluorometer. The above process continues until all grid coordinatesoverlapping the prostate are complete. Each optical sensor measurementwill be correlated to an ultrasound coordinate so that the opticalsensor measurements and the ultrasound image can be overlapped to createthe 3D optical image of the prostate. This is shown in the FIG. 5A whichillustrates a 3D optically mapped image of the prostate followingoptical measurements identifying locations of prostate cancer lesionsaccording to one embodiment. FIG. 5A shows a 3D cross section of XYZcoordinates and FIG. 5A shows tumor volume estimates based on opticalsensor readings. At the completion of optical measurements and tissueclassification using the algorithm, a 3D image of the prostate based onthe optical measurements is generated. Optionally, image analysissoftware can be used to analyze the image of FIG. 5A to generate acorresponding line drawings as shown in FIG. 5B.

Endogenous fluorophores in biological tissues include FAD, NADH,collagen, elastin, tryptophan, tyrosine, phenylalanine, some vitamins,and lipids (which are main components of the cell membrane and someorganelles). Excitation light at 290 and 340 nm is currently being usedto classify prostate cancer tissue limiting us to items which excitenear those wavelengths (see Table 1, below). However, additionalexcitation light sources may be added to excite other types offluorophores to diagnose various other types of cancer based on furtherresearch. See table 1 below for an exemplary listing of endogenousfluorophores which may make up the components of tissue to be evaluationand their excitation maxima and emission maxima.

TABLE 1 Endogenous Excitation Emission fluorophores minima (nm) maxima(nm) Amino Acids Tryptophan 280 350 Tyrosine 275 300 Phenylalanine 260280 Structural proteins Collagen 325 400, 405 Elastin 290, 325 340, 400Enzymes and coenzymes FAD, flavins 450 535 NADH 290, 351 440, 460 NADPH336 464 Vitamins Vitamin A 327 510 Vitamin K 335 480 Vitamin D 390 480

Data processing and a typical tissue classification algorithm are basedon a support vector machine (SVM) or other statistical methods andsystems suitable for classification such as linear discriminant analysis(LDA), artificial neural networks (ANN), multiple logistic regression,etc. Here we describe the procedure for SVM-based tissue classification,although it can be extended to other methods and systems as well. Inmachine learning, support vector machines (SVMs) are supervised learningmodels with associated learning algorithms that analyze data andrecognize patterns, used for classification and regression analysis. Thebasic SVM takes a set of input data and predicts, for each given input,which of two possible classes forms the output, making it anon-probabilistic binary linear classifier. Given a set of trainingexamples, each marked as belonging to one of two categories, an SVMtraining algorithm builds a model that assigns new examples into onecategory or the other. An SVM model is a representation of the examplesas points in space, mapped so that the examples of the separatecategories are divided by a clear gap that is as wide as possible. Newexamples are then mapped into that same space and predicted to belong toa category based on which side of the gap they fall on. In addition toperforming linear classification, SVMs can efficiently performnon-linear classification using what is called the kernel trick,implicitly imaging their inputs into high-dimensional feature spaces.

Below is one example of a software data process of computer executableinstructions stored on a tangible, non-transitory storage medium andexecuted by a processor to validate data based on a support vectormachine (SVM):

-   -   Raw Data such as fluorescence spectra and histopathology of the        tissue score is captured;    -   Conditioning of the raw data includes background subtraction and        S/N ratio cutoff;    -   Preprocessing of the conditioned data involved data smoothing,        interpolation and normalization;    -   Prostate Cancer evaluation includes partial least square (PLS)        analysis of the preprocessed data,    -   Prostate Cancer selection involves statistical analysis of the        evaluated data including reducing false positives (FP) and        reducing false negatives (FN);    -   An algorithm executed on the selected data by a support vector        machine (SVM) analyzes the selected data to provide a binary        classification (cancer/no cancer) of the tissue under        evaluation.    -   Validation of the analyzed data includes statistical analysis by        such techniques as “leave one out” cross-validation and or        external analysis.

FIG. 14 illustrates fluorescence intensity spectra at 290 nm beingprocessed for analysis and classification by 1-step interpolation 142,3-step general average 144, 5-step moving average 146, and backgrounddata 148 which is subtracted. FIG. 15 illustrates fluorescence intensityspectra at 340 nm being processed for analysis and classification by1-step interpolation 152, 3-step general average 154, 5-step movingaverage 156, and background data 158 which is subtracted. FIG. 16illustrates several normalized fluorescence intensity spectra 160 at 290nm excitation being processed for analysis and classification. FIG. 17illustrates several normalized fluorescence intensity spectra 170 at 340nm excitation being processed for analysis and classification. FIGS.18-19 illustrate percentage variability in fluorescence spectra X andhistopathology data Y associated with 1 to 12 PLS components at 290 nmand 340 nm variability, respectively.

In one embodiment, not all components in fluorescence spectra will havethe same “weights.” The partial least squares (PLS) analysis identifieswhich portions of the emission spectra are likely to contain uniquefeatures to help with determining the classification. PLS analysis willcreate a linear combination of weighted values relative to the size ofthe spectral data values. As an example, if there are 1000 discreteintensity values from a single emission spectra, there will be a weightmatrix of the same number of discrete values (in this example, 1000 inall). An algorithm can be configured to focus on the interestedcomponent, say 12 partial least squares components, which in thisexample would create a matrix of size 1000 by 12 where each columnvector represents the linear combination of weighted values for thesingle PLS analysis. FIG. 18 illustrates percentage variability influorescence spectra and histopathology data associated with 1 to 12 PLScomponents. A ranking test such as a Wilcoxon Rank Sum test is then usedto determine which weight vectors are least significantly correlatedsince some features may be redundant due to tracking the identicalfluorophores. Since PLS components for fluorescence spectra at differentexcitations may be correlated, Pearson correlation coefficient is testedto identify such correlations. In the event two PLS components arecorrelated, only one is selected for tissue classification. PLS willinherently create disproportionate weighting of spectral data inattempts of highlighting important features and suppressing lessimportant elements. A feasibility study was conducted duringJuly-December, 2012 to determine the efficacy of an optical biopsyneedle adjunct with fluorescence spectroscopy for diagnosis of prostatecancer. A total of 208 in vivo biopsies (29 malignant) and 224 ex vivobiopsies (51 malignant) were studied. The next two tables summarize riteSVM results for sensitivity (SE), specificity (SP), positive predictivevalue (PPV), negative predictive value (NPV), true positives (TP), truenegative (TN), false positives (FP), and false negatives (FN) based onselected PLS components.

The following Tables 2 and 3 illustrate results as noted above;

TABLE 2 SVM Classification of Benign versus Malignant Disease For InVivo Data PLSC#1-5 PLSC#1-7 PLSC#1-10 TP 17 21 19 TN 118 133 133 FP 2914 14 FN 8 4 6 SP 80% 90% 90% SE 68% 84% 76% PPV 37% 60% 58% NPV 94% 97%96%

TABLE 3 SVM Classification of Benign versus Malignant Disease For ExVivo Data PLSC#1-5 PLSC#1-7 PLSC#1-10 TP 28 26 25 TN 132 136 138 FP 11 75 FN 4 6 7 SP 92% 95% 97% SE 88% 81% 78% PPV 72% 79% 83% NPV 97% 96% 95%

In one embodiment, diffuse reflectance spectra are processed as anadjunct to identify benign versus malignant disease as well as high(Gleason sum≥7) versus low (Gleason sum≤6) disease located up to 1 cmfrom the optical sensor. FIG. 20 shows typical normalized diffusereflectance spectra scans for prostate tissue within the range of 550nm-700 nm for eight (8) normal scans 202 and one cancer indicative scan204. Histopathology of the biopsy core up to 1 cm length is taken intoconsideration for DRS. A total of 263 biopsy cores were analyzedHistopathological analysis classified 151 biopsy cores as benign and 112as malignant. Out of 112 malignant cores, 61 were classified as lowgrade disease (Gleason score≤6) and remaining 51 were classified as highgrade disease (Gleason score≥7). DRS data were processed according tosteps outlined above based on a support vector machine (SVM). PLScomponents were computed and selected as previously described.

FIGS. 21-22 illustrate the percentage variability in DRS andhistopathology data associated with 1 to 12 PLS components for benignversus malignant and high grade versus low grade prostate tissueclassification, respectively. The percent variance is illustrated alongthe y-axis and the number of PLS components is illustrated along thex-axis. FIG. 21 illustrates percentage variability in spectral data Xand histopathology Y associated with each PLS component PLS attempts tominimize least square error while projecting X and Y data. By selectinga combination of PLS components, one can identify a minimum set ofclassifiers that best describe X and Y while keeping the percentagevariability to acceptable levels. In this FIG. 21, PLS components #1-6describes 80% out of 90% total variability of X and 25% out of 30% oftotal variability of Y. Therefore, PLS components #1-6 may be used inSVM for benign versus malignant tissue classification.

Similarly, FIG. 22 illustrates variability in spectral data X andhistopathology Y associated with each PLS component. In this FIG. 22,PLS components #1-7 describes 85% out of 90% total variability of X and48% out of 50% of total variability of Y. Therefore. PLS components #1-7may be used in SVM for low versus high grade cancer tissueclassification.

The following Table 4 summarizes typical values for sensitivity (SE),specificity (SP), positive predictive value (PPV), negative predictivevalue (NPV), true positives (TP), true negative (TN), false positives(FP), and false negatives (FN) obtained for this type of data set.

TABLE 4 Prostate Tissue Classification based on Diffuse ReflectanceSpectra Classification TP TN FP FN SE SP PPV NPV Benign vs. Malignant 73105 57 39 65% 70% 61% 73% Benign vs. Low Grade 44 106 45 17 72% 70% 49%86% Benign vs. High Grade 39 119 32 12 76% 79% 55% 91% High vs. LowGrade 41 49 12 10 80% 80% 77% 83%

FIG. 23 illustrates in block diagram form one embodiment of an opticalsystem 332 such as a fluorometer or a diffuse reflectance spectometerconnected to an optical probe 334 and connected to a computer-basedcontroller 336 executing user interface software and a tissueclassification algorithm. The optical system 332 transmits light from alight source or sources through the probe 334 where light interacts withthe tissue 338 and is received and transmitted back to a detector insidethe optical system 332. The optical system 332 is operated by thecomputer-based controller 336 which processes received signals anddelivers via display 340 diagnostic classification of the tissue underexamination to the user. For example, the display 340 may be an image asillustrated in FIG. 11, 12 or 14-22. Thus, the display 340 presents agraphical user interface which, in its simplest form, is a two (orthree) dimensional image indicate of the condition of the tissue asindicated by the light signal detected by the optical system 332. Forexample, the light signals are indicative of the light emitted,reflected and/or absorbed by the tissue. In addition, an imaging system341 such as an ultrasound system or a MRI/CT system or both incombination has a display 343 which provides a fused US/MRI or US/CTimage for identifying the position of the optical probe 334 relative tothe tissue 338. Alternatively or in addition, the user interface ondisplay 340 can provide the user with options so that the user canselect various images or perspectives of an image. For example, theinterface can give the user the option to select a two-dimensionalimage, a three-dimensional image, a fused image, or some other imagevariation. The interface can also provide the user with the option toselect a black-and-white image, a color image, a line image or otherimage parameter variations.

It is also contemplated that any of the above noted images may becombined or fused with a MRI image or CT image of the same tissue toprovide additional diagnostic and treatment information. For example,FIG. 24B illustrates two photographs, the lower photo 343A is an MRIimage where a cancer lesion was first diagnosed by a radiologist and theupper photo 343B is a MRI fusion image showing a cancer lesion fusedwith an ultrasound (US) image. This combined MRI/US image can be usedfor transrectal or transperineal directed biopsy of the prostate. Whenan optical biopsy needle 334 is used, elastic scattering spectra (e.g.,FIG. 12) can be generated in the computer monitor display 340 from thelocation or vicinity of the cancer lesion shown in MRI/US fusion image.FIG. 24A illustrates one photograph 340A which illustrates elasticscattering spectra. This elastic scattering spectra presented on display340A when processed by a tissue classification algorithm, can eitherconfirm or contradict the existence of a cancer lesion shown in MRI/USfusion image 343B.

As another example, FIG. 25B illustrates two photographs, the lowerphoto 343C is an MRI image w here a cancer lesion was first diagnosed bya radiologist and the upper photo 343D is a MRI fusion image showing acancer lesion fused with an ultrasound (US) image. This combined MRI/USfusion image can be used for transrectal or transperineal directedbiopsy of the prostate. When an optical biopsy needle 334 is used, anadditional fluorescence spectra can be generated in the computer monitordisplay 340 from the location or vicinity of the cancer lesion shown inMRI/US fusion image. FIG. 25A illustrates one photograph 340B whichillustrates fluorescence spectra. This fluorescence spectra presented ondisplay 340 when processed by a tissue classification algorithm caneither confirm or contradict the existence of a cancer lesion shown inMRI/US fusion image 343D.

For example, a system for use with a tissue to create a fused imageincludes the an optical probe array 74 in combination with a MRI or CTimaging guidance system 141 for identifying the position of the opticalprobes relative to the tissue. In addition, an ultrasound imagingguidance system 114 identifies the position of the optical probesrelative to the tissue. A three-dimensional user interface imagingsystem 116 generates a three-dimensional image of the tissue based onthe generated light signals and the identified position of the opticalprobes 74 as indicated by the MRI imaging guidance system 141 and asindicated by the ultrasound imaging guidance system 114. The resultingimages as shown in FIGS. 24-25 are a fusion of an MRI (or CT) imageprovided by the MRI (or CT) imaging guidance system 141 and anultrasound image provided by the ultrasound imaging guidance system 114.As noted herein, MR, CT, or fusion images can be used to guide prostatebiopsies to cancer lesions identified by the radiologists. The opticalbiopsy needle 134 provides additional information by elastic scatteringspectra or fluorescence spectra or both. This information afterprocessed by a tissue classification algorithm indicates whether acancer lesion shown by the images indeed is cancer or not.

Thus, in one form, a system as shown in FIG. 10 is for use with atissue. An optical probe array system 112, 115 has at least two or moreoptical probes for inserting into the tissue, for illuminating thetissue and for generating light signals corresponding to the illuminatedtissue. An imaging system 116, 117 generates an image of the tissuebased on the generated light signals.

Thus, in another form, a system as shown in FIG. 10 is for use with atissue. An optical probe array system 112, 115 has at least two or moreoptical probes for inserting into the tissue, for illuminating thetissue and for generating light signals corresponding to the illuminatedtissue. An imaging system 114, 116, 117 generates an image of the tissuebased on the generated light signals.

Thus, in another form a system as shown in FIG. 13 is for use with atissue 138. An optical probe array system 132 has at least two or moreoptical probes 134 for inserting into the tissue, for illuminating thetissue 138 and for generating light signals corresponding to theilluminated tissue. An imaging system 136, 140 generates an image of thetissue based on the generated light signals.

Thus, in another form, a system as shown in FIG. 23 is for use with atissue 338. An optical probe array system 332 has at least two or moreoptical probes 334 for inserting into the tissue, for illuminating thetissue 338 and for generating light signals corresponding to theilluminated tissue. An imaging system 336, 340, 341, 343 generates animage of the tissue based on the generated light signals.

Thus, in another form, a system as shown in FIG. 23 is for use with atissue 338. An optical probe array system 332 has at least two or moreoptical probes 334 for inserting into the tissue, for illuminating thetissue 338 and for generating light signals corresponding to theilluminated tissue. An imaging system 336, 340 generates an image of thetissue based on the generated light signals.

Thus, in another form, a system as shown in FIG. 23 is for use with atissue 338. An optical probe array system 332 has at least two or moreoptical probes 334 for illuminating the tissue 338 and for generatinglight signals corresponding to the illuminated tissue fluorescenceand/or corresponding to the illuminated tissue diffuse reflectancespectroscopy for distinguishing between cancer tissue and non-cancertissue. A controller 336 and display 340 generate an image correspondingto the generated light signals. An MRI or CT image indicative of theposition of the optical probes relative to the tissue (stored on astorage device) is generated by an imaging system 341. An ultrasoundimaging guidance system for identifying the position of the opticalprobes relative to the tissue is pan of the imaging system 341. Theimaging system 341 generates an image (see photograph 343B, 343D) of thetissue on display 343 based on the identified position of the opticalprobes 334 as indicated by the MRI or CT imaging guidance system 341 andas indicated by the ultrasound imaging guidance system. The generatedimage is a fusion of an MRI or CT image provided by the MRI or CTimaging guidance system and an ultrasound image provided by theultrasound imaging guidance system. A treatment device 339 employing atreatment modality such as described herein can be used in combinationwith the imaged and/or mapped tissue to treat the imaged tissue. Forexample, the device 139 can be a Cryotherapy device; a PhotodynamicTherapy device; a Brachytherapy device; a high-intensity focusedultrasound (HIFU) device; a tissue ablation device; a Laser ablationdevice; a RF ablation device; a Vapor ablation device, and a Local drugdelivery device.

In summary of one embodiment, a physician will introduce the opticalprobe under imaging guidance (e.g. ultrasound, MRI, CT) into specificregions of the prostate using a spatial template. The physician willthen systematically perform an optical sampling of the prostate tocreate a 3-D mapping of the prostate where both benign and malignantsites are identified and recorded. With this 3-D mapping the physiciancan then return to the malignant sites and deploy therapeuticmodalities. Optionally, other images from systems such as MRI and CTscans combined with TRUS image (Image fusion of TRUS and MRI or TRUS andCT) can be communicated into the fluorometer and overlapped with opticalmeasurements.

The measurement points where the tissue classification algorithm hasclassified as abnormal may be displayed with a different color than thenormal tissue. The location of the abnormal tissue with respect totransrectal ultrasound system may also be provided by the optical systemso the physician can easily locate the abnormal tissue under ultrasoundand deliver therapy to the appropriate location.

Design and Materials

The optical probe is an elongated hypodermic needle with a fiber opticbundle passing through an internal bore. The fiber optic bundle iscomprised of at least one transmitter fiber and at least one receiverfiber to form an optical sensor(s). The needle is capable ofaccommodating optical sensors both at the distal tip and variouspositions along its length. The transmitter fiber optics transmit lightfrom a light source or light sources (e.g. light-emitting diode orlaser) to the tissue under examination. Multiple light sources may berouted to the fibers either individually or simultaneously by way ofoptical guides (e.g. focusing lenses or mirrors). The receiver fiberoptics transmit light reflected from or subsequently emitted by thetissue under examination to at least one detector or sensor. The lightsources and light detector are controlled by computer or similarelectronic control that comprises a microprocessor, storage, display,and graphical user interface (GUI). Signals generated by the detectorare processed through a diagnostic algorithm and stored.

The component for generating the 3-D diagnostic mapping couplesdiagnostic information from the spectroscopic evaluation with thespatial location of the respective optical sensors at the time ofacquisition. The 3-D mapping system comprises a computer with graphicaldisplay, graphical user interface, and software that integrates inputsfrom the diagnostic algorithm and the imaging system (e.g. ultrasound orMRI).

In one embodiment, a physician will introduce the optical probe underimaging guidance (e.g. ultrasound, MRI) into specific regions of theprostate using a spatial template. The physician will thensystematically perform an optical sampling of the prostate to create a3-D mapping of the prostate where both benign and malignant sites areidentified and recorded. With this 3-D mapping the physician can thenreturn to the malignant sites and deploy therapeutic modalities. Forexample, the physician would insert a 2×2 probe and the system wouldsequentially excite each of the optical sensors in order to determinethe configuration of tissue adjacent to contiguous to and/or in contactwith the probes. The system knows the position of each sensor relativeto each other and relative to the tissue (based on the USP) and wouldstore the resulting information. Next, the physician would re-insert theprobe at a different, adjacent location and the excitation and measuringprocess would be repeated. Additional insertions may be needed until thetissue of insert is measured and a complete 3-D map is generated.

Integrated 3-D Mapping and Therapy System

The 3-D mapping system can be used with all therapeutic modalities todiagnose and treat prostate cancer patients. The system initiallyoptically maps the prostate and identifies the locals of the abnormaltissue. Either using die same probe with optical sensors or anotherprobe, any of the therapies, such as the mentioned in therapy section ofthis application (or others), may be applied.

Motorized Imaging

Introduction

Prostate cancer is the most frequently diagnosed non-cutaneousmalignancy among U.S. men. In 2015, an estimated 220,800 men will bediagnosed with prostate cancer and 27,540 are expected to the from thisdisease. Undiagnosed prostate cancers are at high risk of spreading andmetastasizing to other organs, in particular to the bone. Therefore,early diagnosis of this disease is critical. The “gold standard” forprostate cancer diagnosis is histopathological assessment of tissueobtained using transrectal ultrasound (TRUS)-guided prostate biopsy.Approximately one million men undergo TRUS-guided prostate biopsies eachyear in the U.S.

TRUS biopsies are taken randomly without targeting specific cancerlesions since TRUS is not designed to accurately identify prostatecancer lesions. TRUS images only show anatomical boundary of theprostate gland for guidance of prostate biopsies. TRUS biopsies may failto provide accurate assessment of the extent of the disease with respectto laterality (unilateral versus bilateral disease) or tumor burden. Onestudy found 66% of patients with unilateral disease on TRUS biopsyfindings had bilateral disease on final pathology after surgery. InitialTRUS biopsies diagnosed all 180 patients with unilateral cancer in thepreviously described study. Among these patients, 110/180 (61.1%) w erelater up-staged to bilateral cancer following TMB. In the studyconducted at the University of Colorado Hospital, 82/180 patients wereup-staged by TMB as a result of either increase in the number ofpositive cores on Transperineal Mapping Biopsy (TMB) by 2 or more thanthat on TRUS biopsy (i.e., tumor burden) or TMB detecting bilateraldisease compared to unilateral disease on TRUS biopsy. The majorshortcomings of current systematic TRUS-guided prostate biopsies can besummarized as follows;

-   -   Low cancer diagnostic yield    -   High false negative rates    -   Over- or underestimate patient's correct Gleason Score    -   Under-sampling of the anterior prostate    -   Systematic targeting of cancer lesions is difficult    -   Failure to provide accurate assessment of the extent of the        disease

The diagnostic accuracy of prostate biopsies can be improved byclassifying underlying tissue as normal versus suspicious using opticalspectroscopy techniques as a precursor to biopsy. There are severaladvantages of using optical spectroscopy for cancer diagnosis; it isquantitative, fast, and sensitive to intrinsic biomarkers of tissue suchas histopathological grade. The light-tissue interaction ischaracterized by the physical nature of light and specific tissuemorphology and composition.

In fluorescence spectroscopy, one or more narrowband light sources areused to excite endogenous fluorophores and the emission spectrum at eachexcitation wavelength is detected. The auto-fluorescence spectra (AFS)depend on several important endogenous fluorophores such as tryptophan,collagen, nicotinamide adenine dinucleotide (NADH), flavin adeninedinucleotide (FAD), and others. Quantitative analysis of AFS obtainedfrom tissue can provide valuable information regarding biochemicalchanges that correlate with disease status. In diffuse reflectancespectroscopy, light is delivered to tissue and after several successivescattering and absorption events it re-emerges from the tissue. Hence,diffuse reflectance spectra (DRS) have information regarding size andshape of cells and intracellular structures of tissue underneath.

Overview of Exemplary Motorized Device

An optical biopsy needle obtains a correlative tissue biopsy core afterthe optical characterization of underlying tissue. The needle uses astandard laboratory fluorometer to collect auto-fluorescence spectra(AFS) and correlative tissue biopsy cores from surgically excisedprostate. Study results showed 86% sensitivity, 87% specificity, 90%negative predictive value, and 83% positive predictive value forseparating malignant cores from benign cores.

A US patent (U.S. Pat. No. 8,406,858 B2) has been awarded to theUniversity of Colorado for the aforementioned optical biopsy needletechnology. Based on this technology, the ClariCore™ Optical BiopsySystem (“ClariCore™ System”) obtains TRUS-guided prostate biopsies inthe clinical settings following optical characterization of underlyingprostate tissue. Optical characterization is binary: either ‘Normal’ or‘Suspicious.’

The ClariCore™ System comprises the following components:

-   -   Optical Biopsy Needle (OBN), which transmits light energy and        performs biopsy    -   Handpiece, which houses the OBN and provides the connection to        the console    -   Console, which provides the primary interface between the user        and device    -   System Software, which contains the analytical algorithm

In one form, the OBN comprises a 16-gauge (1.59 mm) outer cannula and aslightly smaller diameter (1.36 mm) inner needle that houses an opticalsensor. The working length of the needle is 25 cm. The optical sensorutilizes a single 200 μm fiber for tissue excitation as well ascollecting auto-fluorescence spectra (AFS) and diffuse reflectancespectra (DRS). The handpiece has a built-in stepper motor forauto-advancing the inner needle at 1 mm increments up to 18 mm. Thestepper motor is synchronized with the fluorometer for tissue excitationand collecting spectral data at each 1 mm increment. The handpiece hasthree buttons; 1) to initiate auto-advancement of the inner needle withoptical sensor, 2) to release the outer cannula for cutting a tissuecore, and 3) to manually or automatically retract/energize the cannulafor revealing the tissue notch and cocking the device for the nextsample. The handpiece connects to the console via three connectors; onefor excitation transmission through the optical sensor, second forcollecting tissue spectra, and a third for synchronization/communicationof the handpiece electronics with the Console.

The console, with a touch-screen monitor, comprises four main modules:Excitation Unit (EU module 1342), Detection Unit (DU module 1344).Computer Controlled Unit (CCU module 1346) and Master Control Unit (MCUmodule 1348). The EU module 1342 comprises three light sources: 280-290nm and 340 nm excitation sources for AFS and 450-700 nm broadband lightsource for DRS. The DU module 1344 comprises a spectrophotometer tocollect corresponding tissue spectra. The CCU module 1346 comprises acomputer motherboard and associated peripheral devices. The MCU module1348 has its own microcontroller and communicates with and controls theexcitation sources of EU module 1342. It also communicates with thehandpiece 1350 and synchronizes spectral data with the EU module 1342and auto-needle advancing. Main functions of the control board of theMCU module 1348 include synchronization of data collection withauto-needle advancing, optical characterization of tissue, displayresults on the monitor, and user inputs from the monitor. User interfacesoftware supports the Graphical User Interface (GUI) for interactingwith the user.

The components of the ClariCore™ System 1260 in one form are illustratedin FIG. 26.

Use of the ClariCore™ System has been designed to follow standard TRUSbiopsy procedures (FIG. 27).

In one form, the ClariCore™ System, similar to standard TRUS biopsy, isused as follows. With the Optical Biopsy Needle (OBN 1262) inserted inthe ultrasound probe 1270 connected to the ultrasound system 1272, theurologist first manually inserts the OBN 1262 a few millimeters insidethe prostate by piercing through the prostate capsule. The urologist isable to observe the OBN penetration depth on the ultrasound monitor1274. A button on the handle 1264 of the OBN 1262 is depressed toactivate the auto needle advancement mechanism (see FIGS. 33A and 33B)and depressing the button again will cause the needle advancement topause. The built-in auto needle advancing mechanism enables incrementaladvancement of the inner needle in preselected increments (e.g., 1 mmsteps) while capturing optical readings of the underlying tissue aftereach incremental step. The auto needle advancing mechanism willautomatically stop after a preset number of increments (e.g., after the18th 1 mm incremental step). The preset number of increments can beequal to the length of the collection space 1294 (e.g., notch). This isthe stop position for the ClariCore™ System.

At this time, the results of the optical characterization of the tissuewill be displayed to the urologist on the touch-screen monitor. Thenormal/suspicious optical reading is achieved by applying aclassification algorithm to determine whether the tissue is ‘Normal’1282 or ‘Suspicious’ 1284. FIGS. 28A and 28B illustrate thenormal/suspicious optical reading monitor display achieved by applying aclassification algorithm to determine if the tissue is ‘Suspicious’ ateach increment movement of the needle. FIGS. 28A and 28B illustrate 10incremental movements of the needle 1292 which correspond to the 10indications of the tissue classification. Thus, the urologist (anoperator) is able to observe the classification of the tissue within thecollection space 1294 before releasing the cannula 1290 to obtain abiopsy. FIG. 28A illustrates that all 10 tissue classifications C1-C10for the 10 increments are all normal and are illustrated in the samecolor corresponding to normal, such as green. FIG. 28B illustrates thatthe first 3 tissue classifications C1-C3 for the first 3 increments aresuspicious and that last 4 tissue classifications C7-C10 for the last 4increments are suspicious whereas the 3 central tissue classificationsC4-C6 for the 3 central increments are normal. Thus. FIG. 28Billustrates the first 3 and last 4 tissue classifications C1-C3, C7-C10in the same color corresponding to suspicious, such as red, and thecentral three classifications C4-C6 in a different color correspondingto normal, such as green.

On the monitor 1268, each 1 mm of the tissue volume will be denoted in“Green” to indicate ‘Normal’ tissue and in “Red” to indicate‘Suspicious’ tissue. When a biopsy sample is desired, the urologistpresses the second button on the Handle to advance the Cannula (seeFIGS. 33A and 33B) and cut the tissue core. Otherwise, the urologist canremove the Needle 1262 from the prostate without taking a tissue sample.This procedure can be repeated until all preselected biopsy locationsare examined.

There are a number of advantages to using the ClariCore™ System forprostate biopsies previously not available to urologists and patients.The ClariCore™ System provides real-time feedback. If all cores are‘Normal’, the patient can be informed immediately rather than waitingtwo to ten days for the histopathological results. The ClariCore™ Systemmay increase the cancer diagnostic yield of prostate biopsies byfocusing acquisition of biopsy cores from locations indicated as‘Suspicious.’ The ClariCore™ System may reduce the high false negativerates of prostate biopsies by giving the urologist the opportunity toprobe extra locations including the anterior prostate when previouslocations are indicated as ‘Normal.’ Additional probing of new biopsylocations may facilitate increase in suspicious tissue biopsy samplesthereby reducing false negative rates.

If desired, the urologist has the opportunity to probe within thevicinity of location(s) indicated as ‘Suspicious’ when using theClariCore™ System Optical analysis of tissue samples from ‘Suspicious’location(s) and their neighboring locations may lead to betterassessment of the suspicious tissue and aid the pathologists indiagnosing the true extent of the disease with respect to laterality andtumor burden. The ClariCore™ System may eliminate under sampling of theanterior prostate. Some urologists may avoid taking biopsies from theanterior prostate due to fear of perforating the prostate capsule andpenetrating adjacent anatomical structures when activating the biopsygun. However, use of the ClariCore™ System enables the urologist tomaintain a safe distance from prostate boundary when activating thecontrolled needle advancing mechanism and obtaining the tissue core.

Detailed Description of Exemplary Motorized Device

The ClariCore™ System 1260 comprises an Optical Biopsy Needle (OBN) 1262and Handpiece Assembly 1264 that connects to a system Console 1266 (FIG.26). In one form, the system uses non-ionizing LED (light emittingdiode) light sent from an excitation source (in the system Console) tostimulate fluorescence and diffuse reflectance emission from the tissuein contact with the optical sensor at the distal tip of the OBN. Thelight from the emission is transmitted back to the Console to beinterpreted by the algorithm. Based upon the spectral data, thealgorithm classifies the tissue as ‘Suspicious’ or ‘Normal’ and allowsthe physician to perform “targeted” biopsies.

The ClariCore™ System comprises the following components:

-   -   Optical Biopsy Needle (OBN), which transmits light energy and        performs biopsy    -   Handpiece, which houses the OBN and provides the connection to        the console    -   Console, which provides the primary interface between the user        and device    -   System Software, which contains the analytical algorithm

The components of the ClariCore™ System are described below.

Optical Biopsy Needle (OBN)

The OBN is composed of a 16-gauge (1.59 mm) stainless steel Cannula 1290with an open beveled-tip configuration 1291 and a slightly smallerdiameter (1.36 mm) Inner Needle 1292 with embedded optical fiber 1293and a collection space 1294 (a sample notch) for sample collection (19mm sample notch), cable wraps 1295 and connectors 1296 (FIG. 29). Theworking length of the Inner Needle is 25 cm. The optical sensor, at thedistal tip of the Inner Needle, utilizes a single 200 μm fiber fortissue excitation and collecting auto-fluorescence spectra (AFS) anddiffuse reflectance spectra (DRS).

The tip of the OBN contains the single exposed fiber as an opticalsensor 1302 for light source and detection (FIGS. 30 and 31). The outerbeveled Cannula 1290 overlays the Inner Needle 1292 and is used to shearand collect tissue samples. The collection space 1294 (i.e., the samplenotch, 19 mm) at the distal end of the Inner Needle is used to chamberthe excised biopsy core (FIG. 31). The OBN 1262 is integrated into theHandpiece 1264.

Handpiece

The Handpiece 1264 and OBN 1262 have integrated fiber optics, andelectrical and optical cabling to interface with the system console. TheHandpiece 1262 is an enclosed assembly that houses the OBN 1264 (FIG.32). The Handpiece 1262 contains electro-mechanical interfaces (motorand chassis) and has three operational buttons by which the physiciancontrols the advancement of the Inner Needle 1292 (guided by innerneedle sled 1337) and Cannula 1290 (guided by cannula sled 1338) intoselected regions of the prostate tissue under TRUS guidance. The Handle1330 houses the DC stepper motor 1331 (connected to electrical cable1339) for auto-advancing the Inner Needle 1292 in 1 mm increments up to18 mm, see FIGS. 33A and 33B. The stepper motor 1331 is synchronizedwith the fluorometer for tissue excitation and collection of spectraldata at each 1 mm increment. The handpiece 1264 connects to the console1266 via three connectors: one for excitation transmission through theoptical sensor 1302, second for collecting tissue spectra, and a thirdfor synchronization communication of the Handpiece 1264 electronics withthe console 1266.

The Handpiece 1264 has three buttons to control the advancement of theInner Needle 1292 with the optical sensor 1302 (advancement button1333), fire the Cannula 1290 (cannula release button 1334 which allow sa spring to advance the cannula) to obtain a tissue biopsy and to cockthe lever (cannula retraction button 1335) for retracting the Cannula1290 to reveal the Sample Notch 1294 and tissue sample, respectively(FIGS. 33A and 33B). It is contemplated that any advancing device can beused to advance the cannula such as a spring as shown in FIGS. 33A and33B, or a motor, or a combination thereof.

Once the sample has been removed, the physician homes the optical sensor1302 by touching the sensor home tab on the monitor 1268. The built-instepper motor 1331 mechanism in the Handpiece 1264 enables incrementaladvancement of the Inner Needle 1292 in 1 mm steps (up to 18 mm)monitored by advancement sensor 1336 while obtaining optical readings ofthe underlying tissue at each increment. The stepper motor 1331 issynchronized with the EU module 1342 and DU module 1344 in the Console1266 for tissue excitation and collection of spectral data,respectively, at each 1 mm increment. Once the physician receivesspectra or optical characterization of tissue for each 1 mm step, thephysician manually fires the Cannula 1290 to obtain desired tissuesample(s).

The OBN is designed and made of medical grade materials that are widelyused in the medical industry and the Handpiece is made of variousplastic polymers molded parts and metal components.

The OBN/Handpiece Assembly and cables are provided sterile to the useras a single-use, disposable device.

Console

The Console 1266 is housed in a transportable self-contained cabinet.The Console 1266 has a user interface system with display (e.g.,touch-screen monitor 1268), audio components and operation buttons. Asnoted above, there are four main components installed in the Console: anExcitation Unit (EU 1342), Detection Unit (DU 1344), Computer ControlledUnit (CCU 1346) and Master Control Unit (MCU 1348). The CCU module 1346comprises a computer motherboard and associated peripheral devices. Itsmain functions are executing application software for Graphical UserInterface (GUI) and communication with DU, MCU and to external Networks.The MCU communicates with the Handpiece and synchronizes spectral datawith the EU and auto-needle advancing.

FIG. 34 shows the modules of the Console and the hardware interfacescontrolled by the Host and MCU Processors.

The Console 1266 is provided fully assembled (and delivered with amonitor and stand), the Console and accessories are provided non-sterileand are reusable.

System Software with Algorithm

Described at a high level, the primary functions of the System Softwareand Algorithm include:

-   -   1. System software that performs various functions such as        housekeeping functions, taking user inputs and displaying        outputs.    -   2. Algorithm for tissue classification.

The Console 1266 contains a number of software modules. These includesoftware executing on CCU module 1346, MCU module 1348, EU module 1342,and DU module 1344. The user interface software supports GUI forinteracting with the user. It allows user inputs from the monitor 1268including patient data prior to the procedure and display results on themonitor following optical characterization of tissue.

Each functional block represents an independent software item of theConsole 1266. The embedded software for the spectrometer and excitationsource are separate, see FIG. 35. The CCU module 1346 includes aprocessor executing HAS (host application software) instructions 1352for connecting to and coordinating operation between a spectrometer1354, a network user interface software 1356 and the MCU module 1348.The CCU module 1346 includes a resident user interface software and hostboot code instructions. The MCU 1348 module executes MCS (master controlsoftware) instructions for connecting to and coordinating operationbetween the CCU module 1346 and an ESC (excitation source controller).The MCU module 1348 includes MBED libraries and master controller bootcode instructions. In one form, there is a standard TCP/IP socketinterface between the HAS and UI. The resident UI runs on the HostProcessor 1352 and the network UI runs on a separate processor.

CCU or Host Processor and HAS

The CCU module 1346 processor or ‘Host’ processor is the centralcontroller of the system 1260. Software running on the Host processor isdenoted as “Host Application Software” or “HAS”. All supervisory tasks(non-safety critical) are handled by the HAS on the Host processor,which follows the IEC 62304 guidelines pertaining to a Class B device.Any UI designated to run on the Host processor is referred as a“Resident UI.” [Note: Other UI not run on the Host processor arereferred to a “Network UI”.] The Host processor is running the HAS andResident UIs in the CentOS Operating System (OS). The code for the HASis written in C++.

HAS supervises and coordinates the other software modules of the Console1266. The primary responsibilities of HAS include:

-   -   Via communications with the MCS (master control software):        request Handpiece 1264 needle advancements or retractions, set        or retrieve parameters of operation and report system events and        errors;    -   Via communications with the Excitation Source Controller (ESC)        and Spectrometer request turn on/off the UV LEDs, open/close        main shutter through MCU (master control unit), request or        retrieve emission spectral data, disable the ESC or        Spectrometer;    -   Via communications with the UI: send updated procedural        information, report system events and errors and receive command        requests.        HAS Interface to the Algorithm

The system software includes a Tissue Classification Algorithm (TCA)that analyzes the spectra data collected by the Spectrometer. Based uponthe spectral data, the algorithm classifies the tissue. Opticalcharacterization is binary: either ‘Normal’ or ‘Suspicious.’ Thealgorithm/classification software module will classify the measuredoptical signals based on pre-established criteria. The ‘Normal’ or‘Suspicious’ assignment will be based on the optical signal principlecomponent parameters of the measured signal when compared to a thresholdto be derived from pathologically known values of suspicious (orcancerous) and normal (or non-cancerous) measurements in prostatetissue.

The TCA comprises three major components:

-   -   Pre-Processing to remove baseline and DC components of optical        data by use of dark (background) spectral data, and to provide        optical data whitening (normalization). Optical data with very        low signal-to-noise ratio (SNR) are flagged by this step and are        not passed to next steps and as a result are classified as “not        usable”.    -   Spectral Components (Features) Extraction by use of principle        components analysis or similar methods. This step helps to        maintain the necessary information and eliminate redundant and        unnecessary information, which is vital to reduce computational        time and over-training of TCA.    -   Knowledge-based Tissue Classification (kTC) which is a type of        supervised machine learning task of inferring a function from        labeled training data (ground truth). The training data is a set        of training examples, where each example is a pair of data        consisting of a features (Spectral Components) vector and a        desired output value (corresponding histopathological reading of        the same tissue sample). The kTC algorithm analyzes the training        data and produces an inferred function, which can be used to        correctly determine the class labels for unseen (testing) data.        The class labels are ‘Suspicious’ and ‘Normal’. The TCA after        sufficient training and optimization is deployed into HAS (Host        Application Software) for real-time tissue classification to        ‘Suspicious’ and ‘Normal’.

The HAS will provide an interface to call and to execute the Algorithm,passing it the required data acquired from the spectrometer andreceiving the algorithm status. The HAS will have a system event forrelaying the algorithm status to the UI, which can then display thisstatus to the user.

Master Controller Processor and Software (MCS)

The Master Controller Software (MCS) (on the MCU module 1348 processor)is written as a stand-alone operation without an OS. All code is writtenin C++ using the Keil uVision Integrated Development Environment. MCSdirectly interfaces to and controls the Handpiece motor and sensors onthe OBN allowing the user to advance and/or retract it as well as stopit at incremental depths within the tissue under analysis. The MCScontrols the direction, velocity and duration of the Handpiece motor1331 and inputs for optical sensor, advance push-button and Cannulabutton. The MCU also interfaces to the Excitation Source Controller(ESC), which excites the tissue under analysis at each incrementallocation with one of three light sources. The Excitation Source controlsthe excitation light sources (intensity, on/off main shutters andregulation of UV exposure time) with its embedded software. Because ofthe patient risk of injury, the MCS will follow IEC 62304 guidelinespertaining to a Class C device.

Exemplary Motorized Device Characteristics

The ClariCore™ System characteristics are listed in Table 5.

TABLE 5 ClariCore System Characteristics Characteristic DescriptionDesign Biopsy Handpiece with capability of emission of light andcollection of spectra data through fiber optic located at distal tipAnatomic Site Prostate Method of Transrectal Ultrasound (TRUS) guidedplacement Placement Method of Ultrasound Visualization Mechanics of A)Mechanical (spring-activated) biopsy of tissue and Action B) Collectionof spectra data based on the principle of auto-fluorescence and defusereflective Mode of Single puncture/sample Action Relevant Handpiece witha biopsy cannula/needle that contains Characteristics an optical sensorthat is incrementally advanced by 1 mm into the prostate taking spectraat each increment Safety Electro-mechanical interface with software thatFeatures controls on/off of UV LEDs, open/closes main shutter, andelectrical circuits that measure overall exposure can disable theexcitation source Alarms: - Alarms may be included. Examples: an alarmmay be generated if the exposure limit is reached, or if the Console orHandpiece malfunctions.Exemplary System Specifications

Table 6 lists the known component specifications for the ClariCore™System.

TABLE 6 System Specifications by Component OBN/Handpiece AssemblyCannula Size 16-gauge Cannula/Needle Material SS304 Fiber Optics 200 umdiameter, 0.22 NA, High OH Silica, multimode fiber Sample Notch Length19 mm Needle Penetration Depth 22 mm Needle Working Length 25 cm DepthGradations on Centimeter markings Cannula Cable Length 1.8 mSterilization Method EO Operating Voltage 6 V, 1 Amp max HandpieceChassis PC/ABS Console Dimensions 122 cm × 68 cm × 68 cm ElectricalSafety Class II Classification Classification Type BF applied part PowerInput (Voltage, 100-240 V at 50/60 Hz Current) ANSI IESNA RP-27.3-96RG-3 Risk Group Classification and Labeling Mode of Operation ContinuousIngress Protection Rating IPX0 Operating Temperature 10 to 40° C., up to85% RH and Humidity Storage Temperature and −25 to 60° C., up to 90% RHHumidity Excitation Source Source Emission 280 ± 2 nm UVB, 340 ± 2 nmUVA, 450-850 nm VIS/NIR Classification Type BF applied part TBD ANSIIESNA RP-27.3-96 RG-3 TBD Risk Group Classification and Labeling Mode ofOperation Pulse Width Modulation, 40 kHz base frequency Output Power,from fiber UVB −2 uW at 25% of max power, UVA 5 uW at 25% of max power,VIS/NIR 1 uW/3 nm Ingress Protection Rating IPX0 TBD Spectrometer Lightdetection 250 nm to 850 nm Classification Type BF applied part TBD ANSIIESNA RP-27.3-96 TBD Risk Group Classification and Labeling Mode ofOperation TBD Output Power, from fiber 5 v DC ± 5% Ingress ProtectionRating IPX0 TBD Computer Control Unit CCU Subcomponents Motherboard BCMAdvanced Research MX81H CPU Intel Core i5-4570TE processor withHyper-Threading Operating System CentOS 7 Linux Software CustomApplication Software Memory 16 GB - 2 each Micron 8GBMT16KTF1G64HZ-1G6E1SODIMM Storage (internal) Operating System Hard Drive mSATA- 128 GBSanDisk SD7SF6S- 128G-1122 Patient Data Hard Drive 2.5 Solid StateDrive - 512 GB SanDisk SD7SB7S-512G-1122 Storage (external) USB FlashDrive WiFi Intel Wireless-N 7260, IEEE 802.11b/g/n Wi-Fi plus TouchScreen Display Open Frame Display: Apollo Displays POS-Line 10.4″ withTrue Flat Glass and Projective Capacitive touch screen Power SupplyMedical AC/DC Power Supply: Murata 400 W 12 V Output AC/DC Power SupplyConverter MVAC400-12AF MasterControl Unit PCBA Custom PCB assemblyMicrocontroller STMicroelectronics STM32F401 Operating System None -Custom software Power Distribution PCBA Custom PCB assembly Applied PartEMC Filter Custom PCB assembly PCBA Graphical User Interface CustomSoftware (TBD)Exemplary Operation

Mechanical biopsy of tissue and collection of spectra data based on theprinciple of auto-fluorescence, i.e., when energy is applied to tissue,the tissue emits light energy at a specific wavelength intensity andpattern. In fluorescence spectroscopy, one or more narrowband lightsources are used to excite endogenous fluorophores and the emissionspectrum at each excitation wavelength is detected. Theauto-fluorescence spectra (AFS) depend on several important endogenousfluorophores such as tryptophan, collagen, nicotinamide adeninedinucleotide (NADH), flavin adenine dinucleotide (FAD), and others.Quantitative analysis of AFS obtained from tissue can provide valuableinformation regarding biochemical changes that correlate with diseasestatus. In diffuse reflectance spectroscopy, light is delivered totissue and after several successive scattering and absorption events itre-emerges from the tissue. Hence, diffuse reflectance spectra (DRS)have information regarding size and shape of cells and intracellularstructures of tissue underneath. Refer to Appendix A, Mechanism ofAction (Expanded), for additional mechanism of action details.

With the exception of the OBN 1262 there are no other device componentsthat come in contact with the patient's blood or bodily fluids. The user(physician) is gloved while handling the OBN/Handpiece Assembly and theother system components (e.g. monitor).

Exemplary Principles of Operation

Use of the ClariCore™ System has been designed to follow standard TRUSbiopsy procedures (FIG. 27).

When the biopsy procedure is complete, the Handpiece cables are removedfrom the Console and the entire Handpiece is disposed of in accordancewith hospital standards. The protective film is removed from the monitorand disposed of in a biohazard waste container. The user can downloadthe report information via an external USB storage device. Theinformation will be stored on the console for future retrieval, ifdesired. The device is powered off with the power button (andconfirmation of power off sequence is visible on the screen). Refer toAppendix B, Quick Reference Guide, for additional principle ofoperations details.

Exemplary Use/Indications for Use

The ClariCore™ System is designed to perform biopsies of the prostrateand provide adjunctive tissue characterization. The optical spectroscopycomponent is primarily a documentation tool.

The ClariCore™ System is an in vivo real-time tissue-classifying biopsysystem for targeted tissue biopsies. The system is indicated forintraoperative use as an adjunctive diagnostic tool during TRUS guidedprostate biopsy. The system is intended to provide intra-operativetissue characterization of ‘Normal’ versus ‘Suspicious’ in vivo prostatetissue for subsequent excision. The system is to be used in facilitatingtargeted biopsy sampling (which includes submission for histologicalexamination).

Non-/Pre-Clinical Testing

Bench, in vivo (animal), and ex vivo (human prostate and bovine) testingfor the first generation of the ClariCore™ System were performed tovalidate and verify that the system satisfies the performance,functional, and safety requirements relative to the productspecifications, risk analysis, and Instructions for Use. A series ofnon-clinical laboratory studies were performed and included testingrelated to the safety and performance of the first generation system.The testing included electrical safety/electromagnetic compatibility,software verification, mechanical and structural bench testing,biological evaluation, reliability, sterility and stability.Additionally, component and system level in vivo (animal) and ex vivo(human prostate and bovine) tissue testing demonstrated deviceperformance.

Clinical Feasibility Study

The pre/non-clinical testing noted above were used to support an initialhuman, non-significant use clinical study—using the device in an opensurgical setting immediately prior to a patient's already scheduledradical prostatectomy. In one form, the system comprises a core biopsyneedle with fiber optics (optical biopsy needle), fluorometer, andlaptop with operating software. The fiber optics were incorporated intoa general-purpose biopsy needle. The system was used to collect opticalspectral data and a correlative biopsy core from patients undergoingradical retropubic prostatectomy surgery.

The overall objective of the study was to acquire and analyze spectraldata and correlative tissue biopsy cores using the investigationaloptical biopsy needle, fluorometer, and associated software. Thisobjective was achieved by performing prostate biopsies immediately afteroptical spectral data was collected from each of the biopsy locations,on patients scheduled for radical retropubic prostatectomy surgery, justprior to removal of their prostate. The in vivo optical biopsies wereperformed during the surgery as an open procedure while the prostate wasexposed with the blood vessels to the gland not yet severed.Additionally, ex vivo acquisition and analysis of spectral data andcorrelation of tissue biopsy cores were evaluated post-prostatectomysurgery. The initial effectiveness of the optical biopsy system andunderstanding of the inter-patient and intra-patient variations oftissue classification algorithm were evaluated.

Prostate biopsies were grouped into benign or malignant based on thehistological findings within a measurement window 0.5 mm wide andlocated 1.7 mm from each core's distal-end. Partial Least Squaresanalysis of tissue spectra was performed to identify principalcomponents (PCs) as potential classifiers. Using a linear support vectormachine and a leave-one-out cross validation method, selected PCs weretested for their ability to classify benign vs. malignant prostatictissue.

TABLE 10 List of Acronyms AFLS Auto Fluorescence Lifetime SpectroscopyAFS Auto Fluorescence Spectra ASAP Atypical Small Acinar ProliferationAUC Area Under the Curve CCU Computer Control Unit CMs ContractManufacturers CT X-ray Computed Tomography DFMEA Design Failure ModeEffects Analysis DHF Device History File DMR Device Master Record DRSDiffuse Reflectance Spectra DU Detection Unit ESC Excitation SourceController EU Excitation Unit FDA Food & Drug Administration FAD FlavinAdenine Dinucleotide GS Gleason Score GUI Graphical User Interface HGPINHigh-Grade Prostatic Intra-epithelial Neoplasia IDE InvestigationalDevice Exemption IEC International Electrotechnical Commission IHCImmunohistochemical Staining IRB Institutional Review Board ISOInternational Organization for Standardization HAS Host ApplicationSoftware H&E Hematoxylin and Eosin stain HG High Grade KTCKnowledge-based Tissue Classification LED Light Emitting Diodes LG LowGrade LHR Lot History Records MCS Master Controller Software MCU MasterControl Unit MR Magnetic Resonance Mp-MRI Multiparametric MagneticResonance Imaging MRI Magnetic Resonance Imaging NADH NicotinamideAdenine Dinucletide OBN Optical Biopsy Needle OPC Objective PerformanceCriteria OS Operating System OTS Off-the-Shelf PB Precision Biopsy LLCPC Principal Component PET Position Emission Tomography PFMEA ProcessFailure Mode Effects Analysis PIN Prostatic Intra-epithelial NeoplasiaQMS Quality Management System ROC Receiver Operating Curves RRP RadicalRetropubic Prostatectomy SAE Serious Adverse Events SMA Sub-Miniatureversion A SNR Signal to Noise Ratio SVM Support Vector Machine SWSoftware TCA Tissue Classification Algorithm TMB Transperineal MappingBiopsy TRUS Transrectal Ultrasound UIS User Interface Software UVUltraviolet

In one form, the system is for use with a tissue and comprises anoptical probe array system having at least one or more optical probesfor inserting into the tissue, for illuminating the tissue and forgenerating light signals corresponding to the illuminated tissue, and animaging system for generating an image of the tissue based on thegenerated light signals. The optical probe imaging system comprises amotorized handheld device to move the probe and excite the tissue. Theoptical probe imaging system records responses based on location of theoptical probe imaging system relate to the tissue. The optical probeimaging evaluates the generated light signals using a near real-timealgorithm to provide classification of the tissue.

In one form, a method comprises positioning one or more optical lightsources adjacent to or within tissue to illuminate the tissue, andcapturing spectra or other optical phenomena from the illuminated tissueusing a sensor. The method characterizes the tissue at the location ofthe optical sensor based on the captured spectra or other opticalphenomena and determines corresponding coordinates of the tissue to mapa 3D image of the tissue. The 3D optical image of the tissue is createdbased on the mapped 3D image. A motorized handheld device is used tomove the sources within the tissue to excite the tissue. Responses ofthe sensor are recorded based on location of the sources relate to thetissue. The spectra or other optical phenomena from the illuminatedtissue are evaluated using a near real-time algorithm to provideclassification of the tissue.

In one form, the system is for use with a tissue and comprises anoptical probe array system having at least one or more optical probesfor illuminating the tissue and for generating light signalscorresponding to the illuminated tissue fluorescence and orcorresponding to the illuminated tissue diffuse reflectance spectroscopyfor distinguishing between cancer tissue and non-cancer tissue, acontroller and display generating a light signal image corresponding tothe generated light signals, an imaging system including a displaygenerating an MRI or CT image indicative of the position of the opticalprobes relative to the tissue. The, imaging system includes anultrasound imaging guidance system for identifying the position of theoptical probes relative to the tissue wherein the imaging systemgenerates a fused image on its display of the tissue based on theidentified position of the optical probes as indicated by the MRI or CTimaging guidance system and as indicated by the ultrasound imagingguidance system wherein the fused image is a fusion of an MRI or CTimage provided by the MRI or CT imaging guidance system and anultrasound image provided by the ultrasound imaging guidance system. Theoptical probe imaging system comprises a motorized handheld device tomove the probe and excite the tissue. The optical probe imaging systemrecords responses based on location of the optical probe imaging systemrelate to the tissue. The optical probe imaging evaluates the generatedlight signals using a near real-time algorithm to provide classificationof the tissue.

The Abstract and summary are provided to help the reader quicklyascertain the nature of the technical disclosure. They are submittedwith the understanding that they will not be used to interpret or limitthe scope or meaning of the claims. The summary is provided to introducea selection of concepts in simplified form that are further described inthe Detailed Description. The summary is not intended to identifyfeatures or essential features of the claimed subject matter, not is itintended to be used as an aid in determining the claimed subject matter.

For purposes of illustration, programs and other executable programcomponents, such as the operating system, are illustrated herein asdiscrete blocks. It is recognized, however, that such programs andcomponents reside at various times in different storage components of acomputing device, and are executed by a data processor(s) of the device.

Although described in connection with an exemplary computing systemenvironment, embodiments of the aspects of the invention are operationalwith numerous other special purpose computing system environments orconfigurations. The computing system environment is not intended tosuggest any limitation as to the scope of use or functionality of anyaspect of the invention. Moreover, the computing system environmentshould not be interpreted as having any dependency or requirementrelating to any one or combination of components illustrated in theexemplary operating environment. Examples of well-known computingsystems, environments, and/or configurations that may be suitable foruse with aspects of the invention include, but are not limited to,personal computers, server computers, hand-held or laptop devices,multiprocessor systems, microprocessor-based systems, set top boxes,programmable consumer electronics, mobile telephones, network PCs,minicomputers, mainframe computers, distributed computing environmentsthat include any of the above systems or devices, and the like.

Embodiments of the aspects of the invention may be described in thegeneral context of data and/or processor-executable instructions, suchas program modules, stored one or more tangible, non-transitory storagemedia and executed by one or more processors or oilier devices.Generally, program modules include, but are not limited to, routines,programs, components, and data structures that perform particular tasksor implement particular abstract data types. Aspects of the inventionmay also be practiced in distributed computing environments where tasksare performed by remote processing devices that are linked through acommunications network. In a distributed computing environment, programmodules may be located in both local and remote storage media includingmemory storage devices.

In operation, processors, computers and/or servers may execute theprocessor-executable instructions (e.g., software, firmware, and/orhardware) such as those illustrated herein to implement aspects of theinvention.

Embodiments of the aspects of the invention may be implemented withprocessor-executable instructions. The processor-executable instructionsmay be organized into one or more processor-executable components ormodules on a tangible processor readable storage medium which is not asignal. Aspects of the invention may be implemented with any number andorganization of such components or modules. For example, aspects of theinvention are not limited to the specific processor-executableinstructions or the specific components or modules illustrated in thefigures and described herein. Other embodiments of the aspects of theinvention may include different processor-executable instructions orcomponents having more or less functionality than illustrated anddescribed herein.

The order of execution or performance of the operations in embodimentsof the aspects of the invention illustrated and described herein is notessential, unless otherwise specified. That is, the operations may beperformed in any order, unless otherwise specified, and embodiments ofthe aspects of the invention may include additional or fewer operationsthan those disclosed herein. For example, it is contemplated thatexecuting or performing a particular operation before, contemporaneouslywith, or after another operation is within the scope of aspects of theinvention.

All references, including without limitation all papers, publications,presentations, texts, reports, manuscripts, brochures, internetpostings, journal articles, periodicals, and the like, cited in thisspecification are hereby incorporated by reference. The discussion ofthe references herein is intended merely to summarize the assertionsmade by their authors and no admission is made that any referenceconstitutes prior art. The inventors reserve the right to challenge theaccuracy and pertinence of the cited references.

It is intended that all patentable subject matter disclosed herein beclaimed and that no such patentable subject matter be dedicated to thepublic. Thus, it is intended that the claims be read broadly in light ofthat intent. In addition, unless it is otherwise clear to the contraryfrom the context, it is intended that all references to “a” and “an” andsubsequent corresponding references to “the” referring back to theantecedent basis denoted by “a” or “an” are to be read broadly in thesense of “at least one.” Similarly, unless it is otherwise clear to thecontrary from the context, the word “or,” when used with respect toalternative named elements is intended to be read broadly to mean, inthe alternative, any one of the named elements, any subset of the namedelements or all of the named elements.

In view of the above, it will be seen that several advantages of theaspects of the invention are achieved and other advantageous results maybe attained.

Not all of the depicted components illustrated or described may berequired. In addition, some implementations and embodiments may includeadditional components. Variations in the arrangement and type of thecomponents may be made without departing from the spirit or scope of theclaims as set forth herein. Additional, different or fewer componentsmay be provided and components may be combined. Alternatively or inaddition, a component may be implemented by several components.

The above description illustrates the aspects of the invention by way ofexample and not by way of limitation. This description enables oneskilled in the an to make and use the aspects of the invention, anddescribes several embodiments, adaptations, variations, alternatives anduses of the aspects of the invention, including what is presentlybelieved to be the best mode of carrying out the aspects of theinvention. Additionally, it is to be understood that the aspects of theinvention is not limited in its application to the details ofconstruction and the arrangement of components set forth in thefollowing description or illustrated in the drawings. The aspects of theinvention are capable of other embodiments and of being practiced orcarried out in various ways. Also, it will be understood that thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting.

Having described aspects of the invention in detail, it will be apparentthat modifications and variations are possible without departing fromthe scope of the invention as defined in the appended claims. It iscontemplated that various changes could be made in the aboveconstructions, products, and methods without departing from the scope ofaspects of the invention. In the preceding specification, variouspreferred embodiments have been described with reference to theaccompanying drawings. It will, however, be evident that variousmodifications and changes may be made thereto, and additionalembodiments may be implemented, without departing from the broader scopeof the invention as set forth in the claims that follow. Thespecification and drawings are accordingly to be regarded in anillustrative rather than restrictive sense.

What is claimed is:
 1. A system for treating tissue in a patient by auser comprising: an optical probe having at least one light sourceconfigured to illuminate the tissue and at least one sensor for sensingreflected light from the tissue; a spectrometer configured to analyzethe reflected light producing spectroscopic data; and a tissueclassification system comprising at least one algorithm that correlatesselected data of the spectroscopic data with a diagnosis classificationindicative of tissue condition of the tissue based only on the selecteddata, wherein the tissue classification system provides the diagnosisclassification to the user, and wherein the tissue classification systemincludes an imaging system configured to provide the diagnosisclassification to the user by correlating location of the tissue to athree-dimensional image of a portion of the patient's anatomy containingthe tissue, generating a three-dimensional optical spectroscopic imageshowing the location and diagnosis classification of the tissue inrelation to the three-dimensional image and displaying thethree-dimensional optical spectroscopic image.
 2. A system as in claim1, wherein the reflected light comprises Auto-Fluorescence Spectra (AFS)or Elastic Scattering Spectra (ESS).
 3. A system as in claim 1, whereinthe selected data is derived from spectra of endogenous fluorophoresincluding tryptophan, tyrosine, phenylalanine, collagen, elastin, FAD,flavins, NADH, NADPH, Vitamin A, Vitamin K, Vitamin D, pyridoxine,pyridoxamone, pyridoxal, pyridoxic acid, pyridoxal 5′-phosphate, VitaminB12, phospholipids, lipofuscin, ceroid, porphyrins, tryptophan spectraand/or collagen spectra.
 4. A system as in claim 1, wherein thediagnosis classification comprises benign, malignant, abnormal, cancer,disease or calcified.
 5. A system as in claim 1, wherein the diagnosisclassification comprises high grade disease or low grade disease.
 6. Asystem as in claim 1, wherein the optical probe includes a treatmentdevice configured to allow therapeutic treatment to be delivered to thetissue by the treatment device while the optical probe is in position tosense the reflected light for the diagnosis classification.
 7. A systemas in claim 6, wherein the treatment device is configured to deliverlaser energy in a manner that provides laser ablation to the tissue. 8.A system as in claim 6, wherein the treatment device is configured toprovide photodynamic therapy to the tissue.
 9. A system as in claim 8,wherein the treatment device includes an LED at near infrared range todeliver near infrared light to the tissue.
 10. A system as in claim 6,wherein the treatment device is configured to provide brachytherapytherapy to the tissue.
 11. A system as in claim 10, wherein thetreatment device includes a cannula configured to deliver a radioactiveseed therethrough.
 12. A system as in claim 6, wherein the treatmentdevice is configured to deliver ultrasound wave energy in a manner thatprovides high-intensity focused ultrasound therapy to the tissue.
 13. Asystem as in claim 6, wherein the treatment device includes a cryoneedleconfigured for providing cryoablation to the tissue.
 14. A system as inclaim 6, wherein the treatment device includes two or more electrodesconfigured for passing AC or DC current across the tissue to achievetissue ablation.
 15. A system as in claim 6, wherein the treatmentdevice is configured to deliver RF energy in a manner that provides RFablation to the tissue.
 16. A system as in claim 6, wherein thetreatment device is configured to deliver high temperature vapor in amanner that shrinks the tissue as in vapor ablation.
 17. A system as inclaim 6, wherein the treatment device is configured to deliver drugs orpharmaceutical agents to the tissue.
 18. A method of treating tissue ina patient comprising: illuminating the tissue with an optical probe,wherein the optical probe includes at least one sensor for sensingreflected light from the tissue and transmitting reflected lightinformation to a spectrometer configured to analyze the reflected lightproducing spectroscopic data; and receiving a diagnostic classificationof the tissue from a tissue classification system, wherein the tissueclassification system includes at least one algorithm that correlatesselected data of the spectroscopic data with classification data todetermine the diagnostic classification, wherein the classification isindicative of tissue condition based only on the selected data; andwherein the tissue classification system includes an imaging systemconfigured to provide the diagnostic classification to a user bycorrelating location of the tissue to a three-dimensional image of aportion of the patient's anatomy containing the tissue, generating athree-dimensional optical spectroscopic image showing the location anddiagnostic classification of the tissue in relation to thethree-dimensional image and displaying the three-dimensional opticalspectroscopic image, and wherein receiving a diagnostic classificationcomprises viewing the three-dimensional optical spectroscopic image. 19.A method as in claim 18, wherein the reflected light comprisesAuto-Fluorescence Spectra (AFS) or Elastic Scattering Spectra (ESS). 20.A method as in claim 18, wherein the selected data is derived fromspectra of endogenous fluorophores including tryptophan, tyrosine,phenylalanine, collagen, elastin, FAD, flavins, NADH, NADPH, Vitamin A,Vitamin K, Vitamin D, pyridoxine, pyridoxamone, pyridoxal, pyridoxicacid, pyridoxal 5′-phosphate, Vitamin B12, phospholipids, lipofuscin,ceroid, porphyrins, tryptophan spectra and/or collagen spectra.
 21. Amethod as in claim 18, wherein the diagnostic classification comprisesbenign, malignant, abnormal, cancer, disease or calcified.
 22. A methodas in claim 18, wherein the diagnostic classification comprises highgrade disease or low grade disease.
 23. A method as in claim 18, furtherincluding treating the tissue with the use of the optical probe based onthe received diagnostic classification.
 24. A method as in claim 23,wherein the optical probe includes a treatment device configured todeliver laser energy, and wherein treating the tissue comprisesdelivering the laser energy in a manner that provides laser ablation tothe tissue.
 25. A method as in claim 23, wherein the optical probeincludes a treatment device configured to deliver infrared light, andwherein treating the tissue comprises delivering the infrared light in amanner that provides photodynamic therapy to the tissue.
 26. A method asin claim 23, wherein the optical probe includes a treatment deviceconfigured to deliver at least one radioactive seed, and whereintreating the tissue comprises delivering the at least one radioactiveseed to the tissue.
 27. A method as in claim 23, wherein the opticalprobe includes a treatment device configured to deliver ultrasound waveenergy, and wherein treating the tissue comprises delivering theultrasound wave energy in a manner that provides high-intensity focusedultrasound therapy to the tissue.
 28. A method as in claim 23, whereinthe optical probe includes at least one cryoneedle, and wherein treatingthe tissue comprises providing cryoablation to the tissue with the useof the cryoneedle.
 29. A method as in claim 23, wherein the opticalprobe includes a treatment device including two or more electrodesconfigured for passing AC or DC current across the tissue, and whereintreating the tissue comprises passing the AC or DC current across thetissue with the use of the two or more electrodes to achieve tissueablation.
 30. A method as in claim 23, wherein the optical probeincludes a treatment device configured to deliver RF energy, and whereintreating the tissue comprises delivering the RF energy in a manner thatprovides RF ablation to the tissue.
 31. A method as in claim 23, whereinthe optical probe includes a treatment device configure to deliver hightemperature vapor, and wherein treating the tissue comprises deliveringthe high temperature vapor in a manner that shrinks the tissue as invapor ablation.
 32. A method as in claim 23, wherein the optical probeincludes a treatment device configured to deliver drugs orpharmaceutical agents, and wherein the treating the tissue comprisesdelivering the drugs or pharmaceutical agents to the tissue.